Note: Descriptions are shown in the official language in which they were submitted.
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HYDRODYNAMICALLY BALANCING
ORAL DRUG DELIVERY SYSTEM
FIELD OF THE INVENTION
The present invention relates to a gastro-retentive oral drug delivery
system comprising a highly porous matrix comprising at least one drug
substance, sugar(s), gas generating components and optionally, pharmaceuti-
cally acceptable auxiliary components. The pharmaceutical composition,
either in the form of pellets (multiparticulate or single unit dosage form),
beads, granules or capsules, is retained in the stomach while selectively
delivering the drugs) at gastric levels and upper parts of the small intestine
over an extended period of time.
BACKGROUND OF THE INVENTION
An orally administered drug delivery system is exposed to a wide range
of highly variable conditions, such as pH, agitation intensity, gastric
emptying
times and composition of the gastrointestinal fluids during its transit
through
the digestive tract. In addition, presence of food in the tract may affect the
dosage form performance. Therefore, to design an optimum oral controlled
release system it is necessary to take into account the physico-chemical and
physiological environment of the gastrointestinal tract. The conventional
approaches to controlled release formulation known in the art are not
applicable to a variety of drugs having an "absorption window" in the stomach
or upper parts of small intestine. Furthermore, it is advantageous to retain
the
dosage form in the stomach thereby increasing the contact time for local
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activity and to achieve better therapeutic efficacy for the diseases which are
confined to the upper parts of the gastrointestinal tract such as peptic and
duodenal ulcers.
It is readily apparent that a sustained release formulation which slowly
releases medicament over an extended period and is retained in the upper
parts of gastrointestinal tract for a prolonged period would be desirable for
such diseases.
The prior art discloses various approaches for therapeutic dosage
forms which are designed to be retained in the upper parts of the
gastrointestinal tract and possess sustained release characteristics.
U.S. Patent No. 5,780,057 discloses a pharmaceutical tablet having a
multilayer structure wherein at least one layer swells in the presence of
biological aqueous fluids resulting in an increase by at least 50% of the
total
volume of the tablet and thereby allegedly exhibiting a high residence time in
the stomach and/or in the upper portion of the gastrointestinal tract. The
swellable layer, being a granular mixture of biocompatible hydrophilic
polymers and highly swellable (super disintegrating) polymers, allegedly acts
as a barrier and allegedly modulates the slow release of the active ingredient
from the pharmaceutical form. It is believed that the expanded dosage forms
could block the pyloric sphincter or could cause unfavorable conditions
following multiple dosing resulting from retention of swollen dosage units in
the stomach.
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U.S. Patent No. 5,651,985 discloses a composition comprising 30-
90%, by weight of the composition, a homogenous mixture of polymers
containing lactam groups and polymers containing carboxyl groups as gel
forming agents, which swells to form a gel of allegedly high mechanical and
dimensional stability in the aqueous environment of the stomach. It is
believed that as the concentration of the polymers is very high, the dosage
forms containing a high dose medicament would be large and inconvenient for
oral administration.
U.S. Patent No. 5,007,790 discloses a sustained-release oral drug
dosage form comprising a plurality of solid particles of a solid - state drug
dispersed within a hydrophilic, water swellable polymer that swells on
imbibition of gastric fluid to increase the particle size to a level that
promotes
retention in the stomach over said time period, permitting dissolution of the
dispersed drug and release of the resulting solution through a leaching
action.
The swellable polymer also allegedly maintains its physical integrity for at
least a substantial portion of the time period during which the drug is
released
into the stomach and thereafter, rapidly dissolves. It is well recognized by
those skilled in the art that it may be difficult to obtain the desired rate
of
release for a drug that has a high water solubility from such multiparticulate
systems as described in this patent, in which the drug first undergoes
dissolution followed by release of the resulting solution by leaching action.
U.S. Patent No. 5,169,638 discloses a buoyancy controlled release
powder formulation for releasing a pharmaceutical of a basic character
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regardless of the pH of the environment and which formulation includes upto
about 45% by weight of a pH dependent polymer which is a water soluble salt
of a polyuronic acid and upto about 35% by weight of a pH independent
hydrocolloid gelling agent having a viscosity from about 50 to about 100,000
centipoises in a 2% solution at 20°-C. The said formulation allegedly
floats in
the gastric fluid and release the drug at a controlled rate irrespective of
the pH
of the environment. However, the invention is particularly adapted for release
of medicaments of only basic nature. Acidic drugs are not amenable for this
system.
U.S. Patent No. 4,814,179 discloses a floating, sustained release
therapeutic composition in form of a non-compressed tablet having a network
of multitudinous air holes and passages therein and a density of less than one
comprising a matrix containing 0.5 - 4% gelling agent, 10-20% oil, 50-75%
therapeutic agent and water. As exemplified therein, the preparation of non-
compressed tablet requires unconventional processing techniques and uses
molds with cylindrical holes for the same. This involves manufacturing
difficulties and are cost enhancing too.
U.S. Patent No. 4,702,918 discloses a floating, sustained release
formulation formed by heating a mixture of a gelling agent (cellulose or
starch
derivative) and a fat/oil which is solid at room temperature. A sustained -
release capsule dosage form as disclosed therein contains a mixture of (a)
from about 10 to about 90% by weight of a cellulose derivative or a starch
derivative which forms a gel in water and (b) from about 90 to 10% by weight
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of a higher fatty acid glyceride or higher alcohol or a mixture thereof which
is
solid at room temperature and (c) from 0.01 to about 85% by weight of a
pharmaceutical. The capsules are prepared by filling with the said mixture of
(a), (b) and (c), heating to a temperature above the melting point of fatty
acid
glyceride or higher alcohol and cooling and solidifying the said mixture. More
than mere mixing is required to impart buoyancy to the formulation, i.e.,
melting followed by cooling are additional unit operations. The specific
gravity
of digestive fluids especially that of gastric juices is between 1.004 to
1.101. It
is well known to those skilled in the art that it may be difficult to maintain
the
low specific gravity for the sustained release composition as described in
this
patent, for a prolonged period. Further, as also exemplified therein, the
concentration of gelling agents and fat/oil required is high and hence the
system is suited for low dose drugs, while dosage form containing high dose
medicaments would be large and difficult for oral administration.
U.S. Patent No.4,126,672 discloses formulations comprising one or
more medicaments in combination with a hydrocolloid or mixtures of
hydrocolloids so as to have a bulk density less than one and be
hydrodynamically balanced when in contact with gastric fluid. A sustained
release capsule dosage form as described therein comprises finely
particulate, homogenous mixture of chloriazepoxide and diazepam, about 5%
to 60% by weight of therapeutically inert, pharmaceutically acceptable adjunct
materials, about 0% to 60% by weight of a fatty material having a specific
gravity of less than one and about 20% to 75% by weight of one or a mixture
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of hydrocolloids selected from the group consisting of methyl cellulose,
hydroxypropyl cellulose hydroxypropyl methylcellulose, hydroxymethyl
cellulose and sodium carboxymethyl cellulose. Upon contact with gastric
fluid, the hydrophilic colloid hydrates and this hydrated layer allegedly
thereafter slowly dissolves to release the medicament. The release of
medicament is also said to take place by leaching action at or near the
surface. The hydrated colloid allegedly forms an outside barrier which retains
the shape of the capsule and therefore acts to prevent the mass from
disintegrating. However, it is well recognized that the application of such a
system to obtain the desired rate of release of the drug wherein it is
regulated
by the erosion of the polymer, is difficult to maintain.
For the above stated reasons and because the prior art discloses either
complicated devices and systems which are difficult to manufacture on the
industrial scale or the components used therein are not so user friendly, none
of the oral controlled drug delivery systems heretofore described is
completely
satisfactory.
Our co-pending U.S. patent application No. 09/152,932 describes a
pharmaceutical composition in the form of tablets or capsules which provides
a combination of spatial and temporal control of drug delivery when ingested
by a patient. The pharmaceutical composition constitutes an oral controlled
drug delivery system, comprising a drug, a gas generating component, a
swelling agent, a viscolyzing agent and optionally a gel forming polymer. The
viscolyzing agent and the gel forming polymer form a hydrated gel matrix
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which entraps the gas, causing the tablet or capsule to retain in the stomach
or upper part of the small intestine (spatial control) and also creates a
tortuous
diffusion path for the drug, resulting in sustained release of the drug
(temporal
control).
The principle of sustained release which characterizes the formulations
of the subject invention is unique in the art and no teaching has been found
which recognizes the application of such a porous matrix to buoyancy and
sustained release as is taught by the present invention.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a pharmaceutical
composition in the form of pellets, beads, granules or capsules which
constitutes a gastro-retentive oral drug delivery system that
(a) generates a gas to form a highly porous (preferably honeycombed)
matrix with good floating characteristics and also evolves gas upon
contact with gastric fluid which helps in retaining the buoyancy of the
dosage form in the stomach,
(b) provides increased gastric residence and thereby extends residency of
the drug delivery system in the gastrointestinal tract,
(c) delivers the drug at a controlled rate and exhibits reproducibility of
release rate into aqueous media while floating in the stomach and
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(d) provides, as compared to other oral controlled drug delivery systems,
increased absorption of a drug that is absorbed largely from the upper
parts of the gastrointestinal tract.
It is also an object of the present invention to provide a pharmaceutical
composition constituting an oral controlled drug delivery system that
maintains
its physical integrity and dimensional stability when in contact with gastric
fluids. The system remains floating in-vitro in the simulated gastric fluid
till
substantially all the drug is released.
The present invention describes a therapeutic system either in the form
of beads, pellets, or granules filled in a capsule (multiparticulate system)
or
single unit pellets and matrix capsules (monolithic system) which constitutes
an orally administered buoyant delivery system capable of extended retention
in gastric fluids. The delivery system is structurally composed of a highly
porous matrix (preferably honeycombed) with large volume of entrapped air
which makes it light and imparts good floatation characteristics.
The therapeutic system comprises drug, sugar, gas generating compo-
nents and optionally, pharmaceutically acceptable auxiliary components.
The gas generating components used herein are a combination of
atleast one thermostable and atleast one thermolabile agent. During the
preparation of formulation, on exposure to high temperature, the thermolabile
agent generates gas and aids in attaining the porous internal structure, while
the thermostable agent reacts with acidic gastric contents of the stomach to
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evolve gas which helps in maintaining buoyancy of the dosage form. Thus,
the combination of gas generating components permits the therapeutic
system to act as a floating matrix that extends the retention of the dosage
form in the stomach and also prolongs its release in the stomach and upper
parts of the small intestine. That is, the system is not transported past the
"absorption window" prior to releasing all or substantially all of the drug
and
maximum bioavailability is attained.
Preferably, the oral controlled drug delivery system of the present
application which is in the form of multiparticulate or a monolithic system,
comprises an amount ranging from a pharmaceutically acceptable amount up
to 35% of drug, about 5% to about 90% by weight of a sugar, about 1 % to
about 30% by weight of the gas generating components and, pharmaceuti-
cally acceptable auxiliary components.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, the oral pharmaceutical composi-
tion includes at least one drug substance, sugar(s), a combination of gas
generating agents and optionally other pharmaceutical auxiliary components
which may be used by one skilled in the art to formulate the therapeutic
system. The choice of auxiliary components and the amounts to be used are
considered to be within the purview of one skilled in the art. It is to be
borne
in mind, however, that these conventional pharmaceutical auxiliary compo-
nents which might adversely affect the hydrodynamic balance of the
formulation of the present invention are not suitable for use therein.
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The gas evolved during the preparation of the formulation by the gas
generating components causes the system to attain a highly porous structure.
The drug is incorporated within this highly porous, preferably honeycombed
matrix.
The composition may be in the form of pellets, beads or granules filled
within a capsule or a sachet (a multiparticulate drug delivery system) or
matrix
capsules and single unit pellets (monolithic system). The art of producing
spherical pellets by extrusion and spheronisation techniques or spheronisa-
tion using techniques based on high shear granulation or fluidized bed tech-
niques is well known and may be used for the preparation of pellets, beads or
granules in the subject invention. Single unit pellets can be produced on
industrial scale using lozenge and troches cutting machines.
Drugs which are thermostable may be added into the matrix while
thermolabile drugs can be loaded onto the carrier spheres (drug free pellets)
using techniques of drug loading based on fluidized bed principle (equipments
like Glatt) which are well known in the art. The pharmaceutical composition of
the present invention may be in the form of a multiparticulate drug delivery
system (up to 4mm in size pellets, granules or beads) or a single unit form as
matrix capsule or large size pellets (more than 5mm in size). The matrix cap-
sule of the present invention may be produced by filling the powder according
to the invention in a capsule made up of either gelatin, starch or hydroxy-
propyl methylcellulose followed with heat treatment.
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Additional polymers recognized in the art of pharmaceutical compound-
ing for their release retarding properties may also be incorporated into the
gastro-retentive formulation of the present invention. These release retarding
polymers may be hydrophilic or hydrophobic in nature or may be pH depen-
dent or independent polymers. Examples of the polymers suitable for this
invention include hydroxypropyl methylcellulose, hydroxypropyl cellulose,
Eudragit, ethyl cellulose, xanthan gum, and the like.
The pharmaceutical composition of the present invention may be
coated with a film forming polymer to control the release of the drug or to
impart better/improved floating characteristics (which is a result of better
entrapment of the gas) or to improve its organoleptic properties. Furthermore,
the pharmaceutical composition may also contain bioadhesive polymers
incorporated within the coating or present as a film coat on the pellets,
granules, beads or capsules in order to improve its gastro-retentive proper-
ties. In another application, some highly swelling polymers may also be
added to increase the size of the dosage form so as to improve its gastric
retention.
The pharmaceutical composition of the subject invention, when added
to simulated gastric fluids, floats on the fluid till substantially all the
drug is
released. The thermostable gas generating agent included therein reacts with
the acid present in the media and generates gases which become entrapped
within the matrix thereby enhancing the buoyancy of the formulation.
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The various components of the present invention are described in more
details below.
DRUG
According to the present invention, the pharmaceutical composition is
in the form of pellets, beads or granules filled in a capsule, a matrix
capsule or
a matrix pellet, as a single unit that provides controlled release of at least
one
therapeutic agent or drug. The drug may be pharmacologically active itself or
may be converted into the active form by biotransformation in the body. The
drug can be any drug for which therapy would be improved as a result of
controlled drug delivery and increased gastric retention.
The medicament or combination of medicaments which are amenable
to controlled release therapy utilising the novel formulations of the present
invention include any of those suitable for oral administration. The present
invention is not to be construed as being limited to any particular medicament
or class of medicaments.
The gastro-retentive formulations of the subject invention are partic-
ularly amenable to the administration of medicaments which are predomi-
nantly absorbed through the upper portion of the gastro intestinal tract,
drugs
having pH dependent solubility, i.e., more soluble in the gastric pH as
compared to the intestinal pH, drugs having stomach as a site of action which
includes H-2 receptor antagonists, antacids, antimuscarinic agents, proton
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pump inhibitors, drugs active against H. pylori, cytoprotective agents, and
the
like.
Illustrative examples of drugs that are absorbed predominantly from the
upper parts of gastrointestinal tract include ciprofloxacin, cyclosporin,
furose-
mide, metoprolol, oxprenolol, baclofen, allopurinol, sumatriptan, benazepril,
enalapril, quinapril, moexipril, indolapril, olindapril, retinapril,
spirapril, clilaze
prilat, lisinopril, imidapril, benazeprilat, cilazapril, captopril, delapril,
tosinopril,
libenzapril, pentopril, perindopril, altiopril, quinaprilat, ramipril,
spiraprilat,
zofenopril, and the like; all of which are suitable for use in the present
inven
tion.
Drugs having the stomach as site of action include H-2 receptor
antagonists such as ranitidine, famotidine, nizatidine, bifentidine,
erbrotidine,
nifentidine, roxatidine and cimetidine, and the like; proton pump inhibitors
like
omeprazole, lansoprazole, pentoprazole, and the like; antacids like magne-
sium carbonate, aluminium hydoxide, magnesium oxide and simethicone, and
the like; cytoprotectives such as sucralphate, carbenoxolone sodium and
misoprostol, and the like; antimuscarinic agents like pirenzepine, telenzepine
and propanthelene bromide, and the like; drugs active against H. Pylori like
bismuth salts such as bismuth subsalicylate, tripotassium dicitratobismuthate,
ranitidine bismuth citrate, and the like; antibiotics for example
clarithromycin,
amoxycillin, and the like; all of which are suitable for use in the present
invention.
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Other medicaments that are suitable for this invention are drugs having
solubility in acidic pH or ones having specific absorption sites in the upper
part
of the gastro-intestinal tract and those that are subjected to gastro-
intestinal
first pass metabolism (as in some reports stomach absorption is known to
bypass gastrointestinal first pass metabolism) include antihypertensive agents
like verapamil, nifedipine, propranolol, nimodipine, nicardipine, amlodipine,
prazosin, ketanserin, guanabenz acetate, hydralazide, carvedilol, methyldopa,
levodopa, carbidopa; antivirals like acyclovir, inosine, pranobex, zidovudine
(AZT), tribavirin, vidarabine; lipid lowering agents like simvastatin,
pravastatin,
atorvastatin and lovastatin; antipsychotic agents like selegiline; sedatives
like
midazolam; all of which are suitable for use in the present invention.
The drug itself or its pharmacologically active salt or ester can be used
in the present invention. Moreover, combination of drugs that are typically
administered together may be included as the drug component. The amount
of drug is that which is typically administered for a given period of time.
Accordingly, the drug may be present in amount ranging from a pharma-
ceutically acceptable amount up to 35% by weight of the total weight of the
composition.
SUGARS
According to the present invention the pharmaceutical composition
contains sugars which provide low density airy structure of the desired
texture
to the matrix. Sugars preferably comprises a pharmaceutically acceptable
saccharide, including a monosaccharide, a disaccharide, or a polyhydric
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alcohol, and/or mixtures of any of the foregoing. Examples of sugars
preferred for the present invention include sucrose, glucose syrup, corn
syrup,
crystalline fructose, fructose, lactose, dextrose, galactose, maltodextrin,
maltose, and the like, sugar alcohols like sorbitol, mannitol, maltol,
maltitol,
xylitol, lactitol. In more preferred embodiments of the subject invention the
sugar is glucose syrup either in the dried form or as a liquid. Sugars may be
used alone or in combination with other similar sugars to achieve suitable
matrix properties. In one preferred embodiment, sugar which is available
under the brand name Glucidex (Roquette, UK) may be used.
The sugar may be present in an amount from about 5% to about 90%
preferably from about 10% to about 85% and more preferably from about 15%
to about 85% by weight of the total weight of the composition.
GAS GENERATING COMPONENTS
According to the present invention, the pharmaceutical composition
contains a combination of thermolabile and thermostable gas generating
agents which aid in the formation of highly porous, preferably honeycombed
structure and enhances the buoyancy of the formulation. As the name
suggests, the thermolabile gas generating agent produces gas upon exposure
to high temperature (of about or less than 200°C) during heating
operation
while the thermostable agent does not dissociate upon exposure to tempera-
tures stated above and produce gas upon contact with gastric fluid. Examples
of thermolabile gas generating agents that may be used in the present
invention include sodium bicarbonate, sodium glycine carbonate, potassium
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bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium metabisulfite,
and the like. The thermostable gas generating agent interacts with an acid
source triggered by contact with water or simply with gastric acid to generate
carbon dioxide or sulphur dioxide that gets entrapped within the highly
porous,
preferably honeycombed matrix of the composition and improves its floating
characteristics. An example of a thermostable gas generating agent is
calcium carbonate and sulfites such as sodium sulfite.
In those embodiments of the present invention, where the pharma-
ceutical composition is in the form of a capsule, thermostable gas generating
agents may be used alone or in combination with an acid source as a couple.
The acid source may be one or more of edible organic acids, a salt of an
edible organic acid, or mixtures thereof. Examples of organic acids that may
be used as the acid source in the present invention include citric acid or its
salts such as sodium citrate or calcium citrate, malic acid, tartaric acid,
succinic acid, fumaric acid, malefic acid or their salts, and the like. The
organic acid salts which may be used as the acid source in the present
invention include, for example, a mono-alkali salt of an organic acid having
more than one carboxylic acid functional group, a bialkali metal salt of an
organic acid having more than two carboxylic acid functional groups, and the
like.
The gas generating components may be present in amounts from
about 1 % to about 40 % preferably from about 1 % to about 35 % and more
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preferably from about 1 % to about 30% by weight of the total weight of the
composition.
AUXILIARY COMPONENTS
Optionally, other conventional pharmaceutical excipients known in the
art of formulation development such as diluents, release retarding agents,
inert oils, binding agents and spheronising agents may also be incorporated
into the buoyant formulation of the present invention.
According to the present invention, the pharmaceutical composition
may comprise a diluent which is stable to heating operation and form a part of
the highly porous, preferably honeycombed structure. The diluent that may
be used in the present invention, belongs to the class of excipients
recognised
in the art of pharmaceutical compounding. In preferred embodiments of the
present invention, diluent is starch. Examples of starches that may be used in
the present invention include maize starch, rice starch, potato starch or
wheat
starch. Examples of other diluents include dibasic calcium phosphate,
calcium sulfate, powdered cellulose, microcrystalline cellulose, and the like.
The diluent may be present in an amount from about 3% to about 50%
by weight of the total weight of the composition, preferably from about 5% to
about 40% and more preferably from about 7% to about 35% by weight of the
total weight of the composition.
The pharmaceutical composition according to the present invention
may also contain polymers to retard the release of the drug. These polymers
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may be present within the matrix structure of the pellets or capsules or may
be coated onto the composition or may be added in capsule presentations of
the present invention in the powder form. The polymers obtained as aqueous
dispersions may replace water as granulating agent in the pellet preparations.
Solid polymers may be added directly into the powder blend.
The polymers used may be of the hydrophilic or the hydrophobic type
or pH dependent or pH independent in nature. Examples of the polymers
suitable for this invention include the polymers well known in the pharma-
ceutical art for their release retarding properties, for example, cellulose
ethers
as hydroxypropyl celluloses of different grades, hydroxyethylcellulose, methyl-
cellulose, hydroxypropyl ethylcellulose carboxymethyl cellulose, sodium
carboxymethyl cellulose, hydroxyethyl methyl cellulose; acrylic polymers
which are obtained as aqueous dispersions like Eudragit NE30D, Eudragit
RS30D, Eudragit RL30D, Eudragit L30D or available as powders such as
Eudragit RSPO, Eudragit RLPO, Eudragit L10055 (all supplied by Rohm
Pharma, Germany), ethyl cellulose as aqueous dispersion or in powder form.
Examples of highly swellable polymers that may be used in the present
invention include hydroxypropyl methylcellulose of different grades, xanthan
gums, sodium alginate, and the like.
The release retarding polymers may also be selected from the class of
natural gums as karaya gum, locust bean gum, guar gum, gellan gum, and
the like.
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The one or more release retarding agents from the same or two
different classes may be present from about 0.3% to about 25%, preferably
from about 1.0% to about 20% or more preferably from about 1.5% to about
15% by weight of the total weight of the composition.
According to the present invention, the pharmaceutical composition
may further contain a therapeutically inert oil which is solid at room tempera-
ture but softens at higher temperatures, that is, around 50-80°C. The
oil, if
present, acts as a release retarding agent. The oil is preferably, a fully
hydrogenated or partially hydrogenated vegetable fat or oil. Examples of oils
that may be used in the present invention include partially or fully hydro-
genated cottonseed oil, coconut oil, soyabean oil, palm oil, kernel oil,
peanut
oil, sunflower oil, and the like. The oils preferred for the present invention
are
mentioned in the United States Pharmacopoeia as type 1 hydrogenated
vegetable oils. These oils may be used alone or in combination with other oils
having the same characteristics.
The oil may be present in an amount from about 0.2% to about 50%
preferably about 0.2% to about 45% and more preferably about 0.4% to about
35% by weight of the total weight of the composition.
The pharmaceutical composition in the form of beads may also include
a binder to provide cohesiveness to the powder mass. The binders commonly
known to the pharmaceutical art may be used in the present invention.
Examples of the binders are pregelatinised starch, polyvinylpyrollidone,
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hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, starch paste,
gelatin, xanthan gum, acacia, guar gum, and the like.
The binder may be present in amounts from about 0.1 % to about 15%,
preferably about 0.2% to about 12% and more preferably about 0.5% to about
10% by weight of the final weight of the composition.
According to the present invention, the pharmaceutical composition is
prepared either in the form of pellets, granules, beads or as matrix capsules.
The pellet/beads can be prepared using the commonly known techniques for
extrusion and spheronisation and also other granulation techniques. Spher-
onising agents are added to the composition to get uniform spherical granules
or pellets. Commonly used spheronisation aids are microcrystalline cellulose
(Avicel PH 101 of FMC Corpn. and Emcocel 50M or Emcocel 90M of
Mendell), mixture of microcrystalline cellulose and sodium carboxymethyl
cellulose (Avicel RC 591 of FMC Corpn.)
The spheronising agent may be present in amounts from about 1 % to
about 30% preferably from about 2% to about 20% and more preferably from
about 4% to about 15% by weight of the final weight of the composition.
In addition to the above ingredients, pharmaceutical grade magnesium
stearate or stearic acid, and the like as a glidant, talc, and the like as an
anti-
adherent and silicon dioxide or hydrogenated vegetable oil or sodium stearyl
fumarate, and the like as a lubricant may be incorporated in the pharma-
ceutical composition according to this invention.
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The pharmaceutical composition in accordance to the present invention
may be optionally coated with a rapidly dissolving water soluble film coat.
Examples of water soluble polymers include hydroxypropyl methylcellulose,
hydroxypropyl cellulose, and the like. The pharmaceutical composition may
be coated to a weight build up of about 1 % by weight to about 10% by weight,
preferably from about 1 % to about 4% by weight of the total weight of the
composition.
According to the present invention the capsule shell may be of a hard
gelatin or a soft gelatin type. Furthermore, the capsules made of starch or
hydroxypropyl methylcellulose may also be used.
The present invention is illustrated by, but is by no means limited to,
the following examples:
EXAMPLE 1
This example illustrates the present invention in the form of pellets in
which Eudragit NE 30 D has been used as a release retarding polymer in
conjunction with hydrogenated vegetable oil within the matrix. The active
ingredient is Diltiazem Hydrochloride. The pharmaceutical composition is
given in Table 1.
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TABLE 1
INGREDIENTS % W/W
Diltiazem Hydrochloride 20.40
Hydrogenated cottonseed oil (Lubritab)16.48
Starch (Maize) 22.09
Dried Glucose Syrup (Glucidex 16.48
40*)
Pregelatinised starch (Starch 1.32
1500)
Microcrystalline cellulose (Avicel9.88
PH 101 )
Ammonium Bicarbonate 2.75
Calcium Carbonate 4.95
Eudragit NE 30D 5.65 (as solids)
*Dextrose equivalent - 40%
Diltiazem Hydrochloride, Hydrogenated cottonseed oil, Starch, Glucose
syrup, Pregelatinised starch, Microcrystalline cellulose, Ammonium bicarbon-
ate and Calcium carbonate were sieved through a sieve (British Standard
Sieve (BSS) 44; 355 Vim) and mixed. The blend was granulated with Eudragit
NE 30 D dispersion and extruded through an extruder (GA 65, Alexender-
werk) fitted with 3.5 mm roller. The extrudates were spheronised in a
spheronizer (Caleva 120mm) for 20 minutes. The pellets thus obtained were
dried in an oven maintained at 120°-C for 25 minutes. The pellets were
allowed to cool down to room temperature.
The pellets were tested for their floating properties and drug release in
900m1 of 0.1 N HCI using USP Apparatus 2 ( paddle type) at 50 rpm. The
pellets equivalent to 30 mg of Diltiazem Hydrochloride were added to the
dissolution vessel.
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At periodic time intervals the visual observations were made to check
buoyancy of the pellets, if any. It was noted that all the pellets remained
floating until 21 hours. The samples of the dissolution media were
periodically
withdrawn and analysed for Diltiazem content spectrophotometrically. The
results are shown in Table 2.
TABLE 2
TIME (HRS) CUMULATIVE % RELEASE
1 53.95
2 67.95
3 76.91
4 85.00
5 88.42
we~nm c n
This example illustrates the present invention in the form of matrix
capsules using Propranolol Hydrochloride as an active agent. The pharma-
ceutical composition is illustrated in Table 3.
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TABLE 3
INGREDIENTS % W/W
Propranolol Hydrochloride 20.00
Hydrogenated cottonseed oil 22.86
(Lubritab)
Starch (Maize) 14.28
Dried Glucose Syrup (Glucidex28.58
40*)
Ammonium Bicarbonate 7.14
Calcium Carbonate 7.14
*Dextrose equivalent - 40%
Propranolol hydrochloride, Starch, Hydrogenated vegetable oil,
Glucose syrup, Ammonium bicarbonate and Calcium carbonate were together
sieved through a sieve (British Standard Sieve (BSS) 44, 355~m) and mixed.
The blend was manually filled in size-2 gelatin capsules. The average
capsule fill weight of the composition was 320 mg. The filled capsules were
kept in an oven maintained at 110°-C for 2.5 minutes, following which
they
were cooled to room temperature.
The capsules were tested for their buoyancy and drug release in a
900m1 of 0.1 N HCI using USP Apparatus 2 (paddle) at 50 rpm. At periodic
time intervals the visual observations were carried out to see the buoyancy of
the capsules. It was noted that the capsules remained buoyant till 20 hours.
The samples of the media were periodically withdrawn and tested for
propranolol content spectrophotometrically. The dissolution results are
recorded in Table 4.
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TABLE 4
TIME (HRS) CUMULATIVE % RELEASE
1 12.41
2 21.02
4 34.06
20 81.71
EXAMPLE 3
This example illustrates single unit pellets (6 to 8 mm in diameter)
which may be used as single unit dosage forms, containing Diltiazem Hydro-
chloride as an active ingredient. The pharmaceutical composition is
illustrated
in Table 5.
TABLE 5
INGREDIENTS % W/W
Diltiazem Hydrochloride 22.37
Hydrogenated cottonseed oil (Lubritab)10.28
Starch (Maize) 30.30
Dried Glucose Syrup (Glucidex 40*)12.12
Pregelatinised starch (Starch 1500)6.04
Microcrystalline cellulose (EMCOCEL9.62
50M)
Ammonium Bicarbonate 3.87
Calcium Carbonate 5.40
*Dextrose equivalent -40%
Diltiazem Hydrochloride, Hydrogenated cottonseed oil, Starch, Glucose
syrup, Pregelatinised starch, Microcrystalline cellulose, Ammonium bicarbon-
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ate and Calcium carbonate were sieved through 355 ~m mesh (British
Standard Sieve (BSS) 44) and mixed. The blend was granulated with water
to get a dough like consistency. The dough was rolled into cylindrical shape
and small pieces weighing for 30 mg of Diltiazem Hydrochloride were cut out
and manually rolled into spherical shape.
The pellets were dried in an oven maintained at 120°C for 10
minutes
following which they were allowed to cool down to room temperature. The
pellets were characterised for floating and drug release as described in
Example 1. The pellets were found to float on the media for 20 hours. The
dissolution results are recorded in Table 6.
TABLE 6
TIME (HRS) CUMULATIVE % RELEASE
1 36.29
2 52.39
3 67.06
4 75.14
5 82.97
6 86.72
7 87.74
EXAMPLE 4
This example illustrates the capsule type of dosage form in which an
organic acid is used in combination with the gas generating agents as a
couple. The pharmaceutical composition is given in Table 7.
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TABLE 7
INGREDIENTS % W/W
Propranolol Hydrochloride 21.46
Hydrogenated cottonseed oil (Lubritab)28.06
Starch (Maize) 10.52
Dried Glucose Syrup (Glucidex 22.45
40*)
Citric acid, anhydrous 3.51
Ammonium Bicarbonate 7.00
Calcium Carbonate 7.00
* Dextrose equivalent - 40%
All the ingredients were sieved through 355 wm mesh (British Standard
Sieve (BSS), 44) and mixed. The blend was filled manually in size-2 gelatin
capsules. The average fill weight was 320 mg. The capsules were given heat
treatment at 110°-C for 2.5 minutes, following which they were cooled
to room
temperature.
The capsules were tested for in-vitro dissolution and floating charac-
teristics as described in Example 2. The capsules remained floating on the
dissolution media throughout the dissolution test of 24 hours. Dissolution
results are recorded in Table 8.
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TABLE 8
TIME (HRS) CUMULATIVE % RELEASE
1 22.77
2 33.46
4 49.06
6 60.18
73.24
24 86.39
EXAMPLE 5
The present example illustrates the capsule type of dosage form made
5 according to the present invention containing a polymer within the matrix
(xanthan gum) together with the gas generating couple consisting of an
organic acid and the gas generating agents. The blend was filled in size-2
gelatin and size-0 HPMC capsules. Table 9 illustrates the pharmaceutical
composition.
10 TABLE 9
INGREDIENTS % W/W
Propranolol Hydrochloride 19.41
Hydrogenated cottonseed oil (Lubritab)25.38
Starch (Maize) 9.52
Dried Glucose Syrup (Glucidex 20.30
40*)
Citric acid, anhydrous 3.17
Xanthan Gum 9.52
Ammonium Bicarbonate 6.35
Calcium Carbonate 6.35
*Dextrose equivalent - 40%
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All the ingredients were weighed and passed through 355 ~m mesh
(British Standard Sieve (BSS), 44) and mixed. The blend was filled manually
in size-2 gelatin capsules (average fill weight 325 mg) and size-0 Hydroxy-
propyl methylcellulose capsules (average fill weight 520 mg). The capsules
were kept in an oven maintained at 110°- C for 2.5 minutes, following
which
they were cooled to room temperature.
The capsules were tested for floating characteristics and dissolution
profile as described in Example 2. The capsules remained floating on the top
of the media for 24 hours. Dissolution results are recorded in Table 10.
TABLE 10
CUMULATIVE % RELEASE
TIME (HOURS)
SIZE 2 SIZE 0
1 19.02 6.60
2 32.15 19.52
4 57.54 50.24
6 73.42 70.59
10 87.80 88.09
24 92.41 95.08
~Yennm G a
This example illustrates the present invention in the form of capsule
formulation using carvedilol as an active agent. The pharmaceutical composi-
tion is illustrated in Table 11.
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TABLE 11
INGREDIENTS % W/W
Carvedilol 10.00
Dried Glucose Syrup 79.50
Calcium carbonate 6.00
Ammonium bicarbonate 2.00
Sodium Alginate 2.00
Hydrogenated cottonseed oil 0.50
(lubritab)
All the ingredients were sieved through 180 ~ mesh (British Standard
Sieve (BSS), 85) and were blended in a mixer (Turbula mixer) for 30 minutes.
The blend was filled manually in size-0 gelatin capsules. The average fill
weight was 500 mg. The capsules were given heat treatment at 100°-C for
9.0
minutes, following which they were cooled to room temperature.
The capsules were tested for in-vitro drug release in 1000 ml dissolu-
tion media of 0.1 N HCI containing 1 % sodium lauryl sulphate. The USP
apparatus 2 with paddle speed at 50 rpm was used for the study. Paddles
were fixed at 4.5 cm away from the base of the vessel and baskets, capped at
the open end, were used as sinkers. The samples of the media were with-
drawn at prescheduled timings and assayed for carvedilol content spectro-
photometrically. The dissolution results are recorded in Table 12.
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TABLE 12
TIME (HRS) CUMULATIVE % RELEASE
0.5 15.39
1.0 27.83
2.0 47.36
3.0 58.00
4.0 63.34
6.0 71.00
EXAMPLE 7
This example illustrates the present invention in the form of capsule
dosage form. The active ingredient is carvedilol. The pharmaceutical compo-
sition is given in Table 13.
TABLE 13
INGREDIENTS % W/W
Carvedilol 9.99
Dried Glucose Syrup 79.65
Calcium carbonate 5.99
Ammonium bicarbonate 1.99
Xanthan Gum 1.59
Sodium Stearyl fumarate 0.79
The capsule dosage form was prepared as described in Example 6.
The capsules were given heat treatment at 100°-C for 13 minutes,
following
which they were cooled to room temperature.
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The capsules were evaluated for dissolution profile as described in
Example 6. The dissolution results are tabulated in Table 14.
TABLE 14
TIME (HRS) CUMULATIVE % RELEASE
0.5 11.95
1.0 29.63
2.0 63.70
3.0 80.24
4.0 90.34
EXAMPLE 8
This example illustrates the present invention in the capsule dosage
form using pravastatin sodium as the active ingredient. The pharmaceutical
composition is given in Table 15.
TABLE 15
INGREDIENTS % W/W
Pravastatin sodium 8.10
Dried Glucose Syrup 74.77
Calcium carbonate 5.72
Ammonium bicarbonate 1.91
Xanthan Gum 7.62
Hydrogenated cottonseed oil (lubritab)1.91
The pharmaceutical composition was prepared as described in
Example 6. The average fill weight of capsules was 525 mg. The capsules
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were given heat treatment at 100°-C for 7.5 minutes, following which
they were
allowed to cool to room temperature.
The dosage form was characterised for drug release in 1000 ml water
using USP apparatus 2 (paddle type) at 50 rpm. The samples of the media
were withdrawn at regular time intervals and analysed for pravastatin content
spectrophotometrically. The results are shown in Table 16.
TABLE 16
TIME (HRS) CUMULATIVE % RELEASE
0.5 9.15
1.0 19.54
2.0 36.89
3.0 55.19
4.0 74.76
5.0 93.91
EXAMPLE 9
This example illustrates the present invention in the form of matrix
capsules using pravastatin sodium as an active ingredient. The pharma-
ceutical composition is illustrated in Table 17.
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TABLE 17
INGREDIENTS % W/W
Pravastatin sodium 7.73
Dried Glucose Syrup 71.37
Calcium carbonate 5.46
Ammonium bicarbonate 1.82
Xanthan Gum 7.28
Microcrystalline cellulose (Emcocel4.55
90M)
Hydrogenated cottonseed oil (lubritab)1.82
The pharmaceutical composition was prepared as described in
Example 6. The average fill weight of capsules was 550 mg. The capsules
were given heat treatment at 100°C for 7.0 minutes, following which
they were
allowed to cool to room temperature.
The dosage form was evaluated for dissolution profile as described in
Example 8. The dissolution results are recorded in Table 18.
TABLE 18
TIME (HRS) CUMULATIVE % RELEASE
0.5 10.79
1.0 20.68
2.0 39.01
3.0 59.44
4.0 81.75
6.0 99.22
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While the invention has been described by reference to specific
examples, this was for the purpose of illustration only. Numerous alternative
embodiments will be apparent to those skilled in the art and are considered to
be within the scope of this invention.
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