Note: Descriptions are shown in the official language in which they were submitted.
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DRUG DELIVERY DEVICE
FIELD OF THE INVENTION
The present invention relates to a device for the delivery of active
pharmaceutical ingredient(s). The present invention also relates to the use
and method for making the same.
BACKGROUND OF THE INVENTION
Many techniques have been used to provide controlled and sustained-
release pharmaceutical dosage forms in order to maintain therapeutic serum
levels of medicaments and to minimize the effects of missed doses of drugs
caused by a lack of patient compliance and the requirement of decreasing
side effects of drugs by controlling their blood concentration.
For example, there are extended release tablets which have an
osmotically active drug core surrounded by a semipermeable membrane. The
semipermeable membrane acts to delimit a reservoir chamber. These tablets
function by allowing a fluid, such as gastric or intestinal fluid, to permeate
the
coating membrane and dissolve the active ingredient so it can be released
through a passageway in the coating membrane by osmotic tension or if the
active ingredient is insoluble in the permeating fluid, pushed through the
passageway by an expanding agent such as a hydrogel. Some
representative examples of these osmotic tablet devices can be found in U.S.
Patents Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407 and 4,783,337.
The problem with these devices is that they are tedious and difficult to
fabricate. Their efficiency and precision is also in doubt as they have been
known to break up prematurely or retain some of the drug content during
transit in the gastrointestinal tract, which may lead to less drug being
released
and delivered by such devices. It is, therefore, not uncommon for such
devices to contain an overage of drug of at least 10% to account for such
inefficiencies in dose delivery. This practice is not economical and presents
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danger, especially if potent drugs are used, as these devices have been
known to rupture in transit thus releasing excess dose.
There have also been reports on sustained-release devices, such as
tablets coated with a release-controlling coat, matrix tablets comprising
water
soluble polymeric compounds, matrix tablets comprising wax, matrix tablets
comprising water insoluble polymeric compounds and the like. For example,
U.S. Patent No. 3,629,393 (Nakamoto) utilizes a three-component system to
provide slow release tablets in which granules of an active ingredient with a
hydrophobic salt of a fatty acid and a polymer are combined with granules of a
hydrocolloid and a carrier and granules of a carrier and an active or a
buffering agent, which are then directly compressed into tablets.
U.S. Patent No. 3,728,445 (Bardani) discloses slow release tablets
formed by mixing an active ingredient with a solid sugar excipient,
granulating
the same by moistening with a cellulose acetate phthalate solution,
evaporating the solvent, recovering the granules and compressing under high
pressure.
U.S. Patent No. 4,704,285 (Alderman) discloses solid slow release
tablets containing 5-90% hydroxypropyl cellulose ether, 5-75% of an optional
additional hydrophilic colloid, such as hydroxypropylmethyl cellulose, an
effective amount of an active medicament, and optional binders, lubricants,
glidants, fillers, etc.
U.S. Patent No. 6,605,300 is directed to the addition of disintegrants to
premanufactured drug loaded beads which are to be combined with diluent to
make a tablet in order to breakup the tablet and disperse the beads once the
tablet is ingested. In this device, the disintegrants do not modulate the
release of the active pharmaceutical ingredients. They only serve to break up
the tablet in order to disperse the beads.
U.S. Patent No. 6,645,528 teaches porous drug matrices and methods
of manufacture thereof.
These sustained-release devices have difficulty in controlling the
release rate of water soluble or water insoluble active pharmaceutical
ingredient(s) precisely. It is noted that when replacing a multiple times a
day
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dosing with once a day dosing that the loading dose, which is represented by
the first dose of an immediate release multiple times a day product, is
captured to a certain extent by the once a day formulation via a loading dose
effect which is built, ideally, into the formulation. Investigational studies
over a
long period of time were needed to obtain devices with a desired release rate.
The desired release rate being a rate of input and extent of release that
simulate a loading dose effect and an extended release profile while using a
single homogenous unit dose. The difficulty arises because conventional and
current controlled release devices require higher amounts of polymers with
high molecular weight and viscosity-imparting or gelling properties to achieve
true extended release. Unfortunately, such high levels do not result in a
loading dose effect. To obtain a loading dose effect in such devices, a lower
amount of polymer concentration is required or a high amount of water soluble
component must be added to moderate the effect of high concentration of
polymer. However, at these levels, high variability is observed within and
between lots. It is also difficult to obtain a product with a reproducible
release
rate and a loading dose effect. Such products also present problems in
quality control as precise control and reproducibility of release profiles is
difficult.
Conventional controlled release systems using only polymers with
superdisintegrants do not meet the requirements for a stable controlled
release device. Attempts have been made in the prior art to use water
soluble components to modulate the effect of polymers on drug release.
These act by creating tortuous channels through which liquid and dissolved
drug flows.
Devices containing superdisintegrants have been studied in order to
obtain a desired controlled release rate. However, it has been found that
such devices have stability issues and tend to fail the mandatory stability
test
set by ICH and the FDA. Superdisintegrants are very moisture sensitive and
tend to swell in the presence of humidity resulting in the breakup of or, at
the
very least, the cracking of the surface of the device. This compromises the
device and adversely alters the original release rate and drug release
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mechanism built into the device. Such a device fails to capture the loading
dose effect which is represented by the first dose of an immediate release
multiple times a day product which it is meant to replace.
Therefore, there is a need to develop stable drug delivery devices
which exhibit a loading dose effect and an extended release profile, while
using a single unit dose. There is also a need for a device that can be
reproducibly manufactured and have the desired effect through less
administration of the device per day.
SUMMARY OF THE INVENTION
In accordance with an aspect of the present invention, there is provided
a drug delivery device comprising a) one or more water soluble active
pharmaceutical ingredients and/or one or more water insoluble active
pharmaceutical ingredients; (b) one or more superdisintegrants and/or one or
more swelling disintegrants; (c) one or more water soluble polymers and/or
one or more water insoluble polymers; and (d) humectant and/or trehalose.
In accordance with another aspect of the present invention, there is
provided a drug delivery device comprising one or more water soluble active
pharmaceutical ingredients and/or one or more water insoluble active
pharmaceutical ingredients; trehalose; and one or more swelling disintegrants
and/or superdisintegrants to modulate the release of said one or more water
soluble active pharmaceutical ingredients and/or one or more water insoluble
active pharmaceutical ingredients.
In accordance with a further aspect of the present invention, there is
provided a method for providing a tableting granulated excipient for
controlled
release of water soluble active and/or water insoluble active pharmaceutical
ingredients, the method comprising mixing an effective amount of said water
soluble active and/or water insoluble active pharmaceutical ingredients to
render a desired therapeutic effect with a premanufactured granulated
excipient comprising from about 1 to about 90 percent by weight of trehalose
from about 5 to about 95 percent by weight of a super-disintegrant and about
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to about 95 percent by weight water soluble polymer and/or water insoluble
polymer material, and from about 5 to about 70 percent by weight of an inert
pharmaceutical filler and silicone dioxide, and thereafter compressing the
resulting blend to form a tablet.
5 In accordance with another aspect of the present invention, there is
provided a tableting granulated excipient which is free-flowing and directly
compressible for controlled release of water soluble active and/or water
insoluble active pharmaceutical ingredients comprising an effective amount
from about 1 to about 90 percent by weight of trehalose; from about 5 to about
95 percent by weight of a super-disintegrant; and about 5 to about 95 percent
by weight water soluble polymer and/or water insoluble polymer material; from
about 5 to about 75 percent by weight of an inert pharmaceutical filler; and
from 0 to about 35 percent by weight of silicone dioxide.
In accordance with a further aspect of the present invention, there is
provided a controlled release device, comprising a homogenous blend of:
(a) a disintegrant selected from a swelling disintegrant and a super-
disintegrant,
(b) a water soluble polymer, in an amount of from about 20% to about
60% by weight based on the total amount of material in the device,
(c) an active pharmaceutical ingredient selected from a water soluble
active pharmaceutical ingredient and a water insoluble active pharmaceutical
ingredient, and
(d) trehalose, in an amount of from about 5% to about 50% by weight
based on the total amount of material in the device.
In accordance with another aspect of the present invention, there is
provided a method of making a universal tableting granulated excipient, which
is free-flowing and directly compressible, for controlled release of a
therapeutically active medicament selected from a water soluble or an
insoluble therapeutically active medicament comprising:
homogenously blending said therapeutically active medicament with a
premanufactured granulated controlled release excipient comprising from
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about 5 to about 50 percent by weight of trehalose, from about 5 to about 95
percent by weight of a super-disintegrant, about 20 to about 60 percent by
weight of a water soluble polymer material, from about 5 to about 75 percent
by weight of an inert pharmaceutical filler and silicone dioxide, and;
thereafter directly compressing the resulting blend to form a tablet.
In accordance with a further aspect of the present invention, there is
provided a universal tableting granulated excipient, which is free-flowing and
directly compressible, for controlled release of a therapeutically active
medicament selected from a water soluble therapeutically active medicament
or an insoluble therapeutically active medicament, comprising a homogenous
blend of:
from about 5 to about 50 percent by weight of treha lose,
from about 5 to about 95 percent by weight of a super-disintegrant,
from about 20 to about 60 percent by weight of a water soluble polymer
material,
from about 5 to about 75 percent by weight of an inert pharmaceutical
filler, and
from 0 to about 35 percent by weight of silicon dioxide.
The novel features of the present invention will become apparent to
those of skill in the art upon examination of the following detailed
description
of the invention. It should be understood, however, that the detailed
description of the invention and the specific examples presented, while
indicating certain embodiments of the present invention, are provided for
illustration purposes only because various changes and modifications within
the spirit and scope of the invention will become apparent to those of skill
in
the art from the detailed description of the invention and claims that follow.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a pharmaceutical composition
comprising: (a) one or more water soluble active pharmaceutical ingredients
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and/or one or more water insoluble active pharmaceutical ingredients; (b) one
or more superdisintegrants and/or one or more swelling disintegrants; (c) one
or more water soluble polymers and/or one or more water insoluble polymers;
and (d) humectant and/or trehalose. The composition may be used for
delivering one or more active pharmaceutical ingredients. Optional
components may be added to the composition, for example, and without
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being limited thereto, silicone dioxide, one or more inert pharmaceutical
fillers,
and/or one or more oil components.
More specifically, the pharmaceutical composition can be used in any
drug delivery device such as, and without being limited thereto, a sustained
release, pulsed release, delayed release and/or controlled release device that
controls the release of one or more active pharmaceutical ingredients. The
device can be a solid unit dosage form. The device can be selected from one
or more granules, one or more compressed tablets, one or more pellets
and/or one or more capsules. In a specific embodiment, the device is a stable
single homogeneous unit controlled release device which controls the release
rate, without significant variability, and with a reproducible controlled
release
rate and a loading dose effect of water soluble and/or insoluble active
pharmaceutical ingredients.
The pharmaceutical composition may be administered in any suitable
manner. For example and without being limited thereto, the composition can
be in the form of a suitable device for oral, vaginal, anal, ocular,
subcutaneous, intramuscular administration or for implantation.
The term "sustained release", "pulsed release", "delayed release" and
"controlled release" are used interchangeably in this application and are
defined for purposes of the present invention as the release of the drug from
the dosage form at such a rate that when a dose of the drug is administered in
the sustained release, pulsed release, delayed release or controlled-release
form, blood (e.g., plasma) concentrations (levels) of the drug are maintained
within the therapeutic range but below toxic levels over a selected period of
time.
The term "swelling disintegrant" and "expanding disintegrant" are also
used interchangeably in this application.
The use of humectant(s) and/or trehalose may be used to stabilize the
combination of superdisintegrant(s) and water soluble and/or water insoluble
polymer(s) and optionally an oil component for the controlled or sustained
release of water soluble and/or water insoluble active pharmaceutical
ingredient(s).
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Trehalose is a disaccharide composed of two glucose molecules bound
by an a,a-1,1 linkage. Since the reducing end of a glucosyl residue is
connected with the other, trehalose has no reducing power. Trehalose is
widely distributed in nature. It is known to be one of the sources of energy
in
most living organisms and can be found in many organisms, including
bacteria, fungi, insects, plants, and invertebrates. Furthermore, trehalose
protects organisms against various stresses, such as dryness, freezing, and
osmopressure. In the case of resurrection plants, which can live in a dry
state, when the water dries up, the plants dry up too. However, they can
successfully revive when placed in water. The anhydrobitic organisms are
able to tolerate the lack of water owing to their ability to synthesize large
quantities of trehalose, and the trehalose plays a key role in stabilizing
membranes and other macromolecular assemblies under extreme
environmental conditions. Trehalose has high thermostability and a wide pH-
stability range. Therefore, it is one of the most stable saccharides.
Trehalose has a very high glass transition temperature compared to
other disaccharides. This allows trehalose to remain stable under a greater
range of temperature extremes. Trehalose dihydrate is stable up to 94%
relative humidity. The low hygroscopic nature of trehalose dihydrate results
in
a free-flowing stable dry product.
In an embodiment, the drug delivery device comprises (a) one or more
water soluble active pharmaceutical ingredients and/or one or more water
insoluble active pharmaceutical ingredients; (b) one or more
superdisintegrants and/or one or more swelling disintegrants; (c) one or more
water soluble polymers and/or one or more water insoluble polymers; and (d)
trehalose. The device may further comprise other excipients such as one or
more oil components and/or silicone dioxide.
Superdisintegrant(s) and/or swelling disintegrant(s) are used in
combination with water soluble and/or water insoluble polymers, instead of
water soluble components or low amounts of polymers, to obtain the desired
release rate of input and extent of release that simulate a loading dose
effect
such that an extended release profile could be achieved using a single
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homogenous unit dose. Superdisintegrants and/or swelling disintegrant(s)
are able to moderate the negative effect of high concentration of polymer and
allow better control of drug release albeit with the disadvantage that the
presence of superdisintegrants and/or swelling disintegrant(s) introduces
stability issues and truncated shelf life. Typically, superdisintegrants
and/or
swelling disintegrant(s) present in the device make it reactive to levels of
relative humidity that it would otherwise not react to. Such devices may
disintegrate or breakup during storage.
Without being limited thereto, it is believed that the combination of
swelling/expanding disintegrant(s) and/or superdisintegrant(s) and water
soluble and/or water insoluble polymers improve and modulate the release of
the active pharmaceutical ingredient(s) while trehalose and/or one or more
humectants are used to stabilize the device and the disintegrants from
adverse relative humidity effects, which are common with systems containing
superdisintegrants. The addition of a humectant and/or trehalose can
decrease moisture sensitivity and enhance product stability.
In another embodiment, the present invention also relates to a drug
delivery device comprising one or more water soluble active pharmaceutical
ingredients and/or one or more water insoluble active pharmaceutical
ingredients; trehalose; and one or more swelling disintegrants and/or
superdisintegrants to modulate the release of said one or more water soluble
active pharmaceutical ingredients and/or one or more water insoluble active
pharmaceutical ingredients. The swelling disintegrants and/or
superdisintegrants can modulate the release of the water soluble active
pharmaceutical ingredients and/or water insoluble active pharmaceutical
ingredients in order to produce multiple peaks. Multiple peaks can
encompass first releasing the active pharmaceutical ingredients from the
device and reaching a peak, and then another starts, releasing the active
pharmaceutical ingredients, which peaks as the previous one is declining.
The present invention also relates to a tableting granulated excipient
for use as a controlled release excipient, the tableting granulated excipient
comprises one or more superdisintegrants and/or one or more swelling
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disintegrants; one or more water soluble polymers and/or one or more water
insoluble polymers; and humectant and/or trehalose. In a more specific
embodiment, the tableting granulated excipient comprises trehalose, one or
more superdisintegrants, and one or more water soluble polymers and/or one
or more water insoluble polymers. Optionally, an inert pharmaceutical filler
and/or silicone dioxide may also be included in the excipient.
The tableting granulated excipient is typically free-flowing and directly
compressible for use as a controlled release excipient.
There are no specific restrictions as to the methods of manufacture of
the composition, device or excipient of the present invention. Typically, the
device can be easily prepared, for instance, by the dry or wet granulation of
a
mixture containing (a) one or more water soluble active pharmaceutical
ingredients and/or one or more water insoluble active pharmaceutical
ingredients; (b) one or more superdisintegrants and/or one or more swelling
disintegrants; (c) one or more water soluble polymers and/or one or more
water insoluble polymers; and (d) humectant and/or trehalose. Optional
components may be added such as, and without being limited thereto,
silicone dioxide, one or more excipients, one or more oil components, and/or
the like. The granules thus obtained are dried if required and passed through
a mill and lubricated. The granules are compressed into a shaped form in a
rotary tablet press using a conventional method.
In another embodiment, the device can be prepared by direct
compression of a mixture containing (a) one or more water soluble active
pharmaceutical ingredients and/or one or more water insoluble active
pharmaceutical ingredients; (b) one or more superdisintegrants and/or one or
more swelling disintegrants; (c) one or more water soluble polymers and/or
one or more water insoluble polymers; and (d) humectant and/or trehalose.
Optional components may be added such as, and without being limited
thereto, silicone dioxide, one or more excipients, one or more oil components,
and/or the like. The controlled release device thus prepared can be used as it
is, or further film-coated.
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In the preparation of the device, the device may be cured at a
predetermined temperature and relative humidity for a predetermined period
of time in order to decrease or increase the rate of release of active
pharmaceutical ingredient(s) from the device.
In the device of the present invention, an ideal release rate for
individual active pharmaceutical ingredients can be ensured by controlling its
release rate by changing the ratio of one or more superdisintegrants and/or
one or more swelling disintegrants; to one or more water soluble polymers
and/or one or more water insoluble polymers; to humectant and/or trehalose;
and to optional components, if any. In certain embodiments, there is about
0.001 wt% to about 60 wt% of one or more water soluble active
pharmaceutical ingredients and/or one or more water insoluble active
pharmaceutical ingredients; about 1 wt% to about 90 wt% of one or more
superdisintegrants and/or one or more swelling disintegrants; about 5 wt% to
about 95 wt% of one or more water soluble polymers and/or one or more
water insoluble polymers; and about 1 wt% to about 90 wt% of humectant
and/or trehalose, based on the weight of the device. Typically, there is about
3 wt% to about 30 wt% of one or more water soluble active pharmaceutical
ingredients and/or one or more water insoluble active pharmaceutical
ingredients; about 5 wt% to about 50 wt% of one or more superdisintegrants
and/or one or more swelling disintegrants; about 5 wt% to about 30 wt% of
one or more water soluble polymers and/or one or more water insoluble
polymers; and about 5 wt% to about 50 wt% of humectant and/or trehalose,
based on the weight of the device.
Swelling disintegrants or superdisintegrants which are used in the
present invention may be any suitable swelling disintegrants or
superdisintegrants that can improve and modulate the release of the active
pharmaceutical ingredient(s). For example and without being limited thereto,
sodium starch glycolate, sodium croscarmellose, homopolymer of cross-linked
N-vinyl-2-pyrrolidone, and alginic acid, a cross-linked cellulose, a cross-
linked
polymer, a cross-linked starch, ion-exchange resin and combinations thereof,
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as well as other conventional Swelling disintegrants or superdisintegrants
well
known to persons skilled in the art.
Exemplary non-limiting humectants which may be useful according to
the present invention may be selected from a wide range of materials such as
glycerin (glycerol), propylene glycol (PEG), ethylene glycol, mineral oil,
lanolin, sorbitol, maltitol, sodium PCA, 1,3-butylene glycol, polyethylene
glycol, polypropylene glycol, lactitol, and triacetin, as well as other
conventional humectants well known to persons skilled in the art.
Water soluble polymers which are used in the present invention may
be any polymers which are soluble in water and can preferably retard the
release of active pharmaceutical ingredients when made into shapes by
press-molding. Preferred water soluble polymers are those which can form
hydrocolloid when molded into shape, thereby retarding release of
pharmaceutically active components. They include naturally occurring or
synthetic, anionic or nonionic, hydrophilic rubbers, starch derivatives,
cellulose derivatives, proteins, and the like. Specific examples are acacia,
tragacanth, xanthan gum, locust bean gum, guar-gum, karaya gum, pectin,
arginic acid, polyethylene oxide, Carbomer, polyethylene glycol, propylene
glycol arginate, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl
cellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium,
polyvinylpyrrolidone, carboxyvinyl polymer, sodium polyacrylate, alpha starch,
sodium carboxymethyl starch, albumin, dextrin, dextran sulfate, agar, gelatin,
casein, sodium casein, pullulan, polyvinyl alcohol, deacetylated chitosan,
polyethyoxazoline, poloxamers and the like. Of these, preferable are
hydroxyethyl cellulose, xanthan gum, hydroxypropyl methylcellulose,
methylcellulose, hydroxypropyl cellulose, carbomer, polyethylene glycol,
poloxamers, polyethylene oxide, starch derivatives and polyvinylpyrrolidone.
These water soluble polymers can be used either singly or in combinations of
two or more.
Water insoluble polymers which are used in the present invention may
be any polymers which are insoluble in water and can preferably retard the
release of active pharmaceutical ingredients. Specific examples of water
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insoluble polymers are, ethylcellulose, chitin, chitosan, cellulose esters,
aminoalkyl methacrylate polymer, anionic polymers of methacrylic acid and
methacrylates, copolymers of acrylate and methacrylates with quaternary
ammonium groups, ethylacrylate methylmethacrylate copolymers with a
neutral ester group, polymethacrylates, surfactants, aliphatic polyesters,
zein,
polyvinyl acetate, polyvinyl chloride, and the like. Preferred water insoluble
polymers are, ethylcellulose, cellulose acetate, polymethacrylates and
aminoalkyl methacrylate copolymer.
Oil components which can be used in the present invention include oils
and fats, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters,
metal salts of higher fatty acids, and the like. Specific examples of oils and
fats include plant oils, such as cacao butter, palm oil, Japan wax (wood wax),
coconut oil, etc.; animal oils, such as beef tallow, lard, horse fat, mutton
tallow, etc.; hydrogenated oils of animal origin, such as hydrogenated fish
oil,
hydrogenated whale oil, hydrogenated beef tallow, etc.; hydrogenated oils of
plant origin, such as hydrogenated rape seed oil, hydrogenated castor oil,
hydrogenated coconut oil, hydrogenated soybean oil, etc.; and the like. Of
these hydrogenated oils are preferred as an oil component of the present
invention. Specific examples of waxes include plant waxes, such as carnauba
wax, candelilla wax, bayberry wax, auricurry wax, espalt wax, etc.; animal
waxes, such as bees wax, breached bees wax, insect wax, spermaceti,
shellac, lanolin, etc.; and the like. Of these preferred are carnauba wax,
white
beeswax and yellow beeswax. Paraffin, petrolatum, microcrystalline wax, and
the like, are given as specific examples of hydrocarbons, with preferable
hydrocarbons being paraffin and microcrystalline wax. Given as examples of
higher fatty acids are caprilic acid, undecanoic acid, lauric acid, tridecanic
acid, myristic acid, pentadecanoic acid, palmitic acid, malgaric acid, stearic
acid, nonadecanic acid, arachic acid, heneicosanic acid, behenic acid,
tricosanic acid, lignoceric acid, pentacosanic acid, cerotic acid,
heptacosanic
acid, montanic acid, nonacosanic acid, melissic acid, hentriacontanic acid,
dotriacontanic acid, and the like. Of these, preferable are myristic acid,
palmitic acid, stearic acid, and behenic acid. Specific examples of higher
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alcohols are lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl
alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl
alcohol,
arachyl alcohol, behenyl alcohol, carnaubic alcohol, corianyl alcohol, ceryl
alcohol, and myricyl alcohol. Particularly preferable alcohols are cetyl
alcohol,
stearyl alcohol, and the like. Specific examples of esters are fatty acid
esters,
such as myristyl palnnitate, stearyl stearate, myristyl myristate, behenyl
behenate, ceryl lignocerate, lacceryl cerotate, lacceryl laccerate, etc.;
glycerine fatty acid esters, such as lauric monoglyceride, myristic
monoglyceride, stearic monoglyceride, behenic monoglyceride, oleic
monoglyceride, oleic stearic diglyceride, lauric diglyceride, myristic
diglyceride, stearic diglyceride, lauric triglyceride, myristic triglyceride,
stearic
triglyceride, acetylstearic glyceride, hydoxystearic triglyceride, etc.; and
the
like. Glycerine fatty acid esters are more preferable. Specific examples of
metal salts of higher fatty acid are calcium stearate, magnesium stearate,
aluminum stearate, zinc stearate, zinc palmitate, zinc myristate, magnesium
myristate, and the like, with preferable higher fatty acid salts being calcium
stearate and magnesium stearate.
These oil components and water insoluble polymers can be used either
singly or in combinations of two or more.
As used herein, the term "active pharmaceutical ingredient" or "active
pharmaceutical ingredients" refers to chemical or biological molecules
providing a therapeutic, diagnostic, or prophylactic effect in vivo. Non-
limiting
active pharmaceutical ingredients contemplated for use in the compositions
described herein include the following categories and examples of drugs and
alternative forms of these drugs such as alternative salt forms, free acid
forms, free base forms, and hydrates: analgesics/antipyretics (e.g., aspirin
TM,
acetaminophen, ibuprofen, naproxen sodium, buprenorphine, propoxyphene
hydrochloride, propoxyphene napsylate, meperidine hydrochloride,
hydromorphone hydrochloride, morphine, oxycodone, codeine,
dihydrocodeine bitartrate, pentazocine, hydrocodone bitartrate, levorphanol,
diflunisal, trolamine salicylate, nalbuphine hydrochloride, mefenamic acid,
butorphanol, choline salicylate, butalbital, phenyltoloxamine citrate,
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diphenhydramine citrate, methotrimeprazine, cinnamedrine hydrochloride, and
meprobamate); antiasthamatics (e.g., ketotifen and traxanox); antibiotics
(e.g.,
neomycin, streptomycin, chloramphenicol, cephalosporin, ampicillin,
penicillin,
tetracycline, and ciprofloxacin); antidepressants (e.g., nefopam, oxypertine,
doxepin, amoxapine, trazodone, amitriptyline, maprotiline, pheneizine,
desipramine, nortriptyline, tranylcypromine, fluoxetine, doxepin, imipramine,
imipramine pamoate, isocarboxazid, trimipramine, venlafaxine, paroxetine,
and protriptyline); antidiabetics (e.g., sulfonylurea derivatives); antifungal
agents (e.g., griseofulvin, amphotericin B, nystatin, and candicidin);
antihypertensive agents (e.g., propanolol, propafenone, oxyprenolol,
reserpine, trimethaphan, phenoxybenzamine, pargyline hydrochloride,
deserpidine, diazoxide, guanethidine monosulfate, minoxidil, rescinnamine,
sodium nitroprusside, rauwolfia serpentina, alseroxylon, and phentolamine);
anti-inflammatories (e.g., (non-steroidal) indomethacin, flurbiprofen,
naproxen,
ibuprofen, ramifenazone, piroxicam, (steroidal) cortisone, dexamethasone,
fluazacort, celecoxib, rofecoxib, hydrocortisone, prednisolone, and
prednisone); antiteoplastics (e.g., cyclophosphamide, actinomycin, bleomycin,
daunorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil,
carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide,
camptothecin and derivatives thereof, phenesterine, paclitaxel and derivatives
thereof, docetaxel and derivatives thereof, vinblastine, vincristine,
tamoxifen,
and piposulfan); antianxiety agents (e.g., lorazepam, prazepam,
chlordiazepoxide, oxazepam, clorazepate dipotassium, diazepam,
hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol,
halazepam, chlormezanone, and dantrolene); immunosuppressive agents
(e.g., cyclosporine, azathioprine, mizoribine, and FK506 (tacrolimus));
antimigraine agents (e.g., ergotamine, divalproex, isometheptene mucate, and
dichloralphenazone); sedatives/hypnotics (e.g., barbiturates such as
pentobarbital, pentobarbital, and secobarbital; and benzodiazapines such as
flurazepam hydrochloride, triazolam, and midazolam); antianginal agents
(e.g., beta-adrenergic blockers; calcium channel blockers such as nisoldipine;
and nitrates such as nitroglycerin, isosorbide dinitrate, pentaerythritol
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CA 02576556 2007-02-01
tetranitrate, and erythrityl tetranitrate); antipsychotic agents (e.g.,
haloperidol,
loxapine succinate, loxapine hydrochloride, thioridazine, thioridazine
hydrochloride, thiothixene, fluphenazine, fluphenazine decanoate,
fluphenazine enanthate, trifluoperazine, chlorpromazine, perphenazine,
lithium citrate, respiridone, and prochlorperazine); antimanic agents (e.g.,
lithium carbonate); antiarrhythmics (e.g., bretylium tosylate, esmolol,
amiodarone, encainide, digoxin, digitoxin, mexiletine, disopyramide
phosphate, procainamide, quinidine sulfate, quinidine gluconate, quinidine
polygalacturonate, flecainide acetate, tocainide, and lidocaine);
antiarthritic
agents (e.g., phenylbutazone, sulindac, penicillamine, salsalate, piroxicam,
azathioprine, indomethacin, meclofenamate, gold sodium thiomalate,
auranofin, aurothiogiucose, and tolmetin sodium); antigout agents (e.g.,
colchicine, and allopurinol); anticoagulants (e.g., heparin, heparin sodium,
and
warfarin sodium); thrombolytic agents (e.g., urokinase, streptokinase, and
alteplase); antifibriolytic agents (e.g., aminocaproic acid); hemorheologic
agents (e.g., pentoxifylline): antiplatelet agents (e.g., aspirin);
anticonvulsants
(e.g., valproic acid, divalproex sodium, phenyloin, phenyloin sodium,
clonazepam, primidone, phenobarbitol, amobarbital sodium, methsuximide,
metharbital, mephobarbital, mephenyloin, phensuximide, paramethadione,
ethotoin, phenacemide, secobarbitol sodium, clorazepate dipotassium, and
trimethadione); antiparkinson agents (e.g., ethosuximide);
antihistamines/antipruritics (e.g., hydroxyzine, diphenhydramine,
chlorpheniramine, brompheniramine maleate, cyproheptadine hydrochloride,
terfenadine, clemastine fumarate, triprolidine, carbinoxamine,
diphenylpyraline, phenindamine, azatadine, tripelennamine,
dexchlorpheniramine maleate, methdilazine, loratadine, and); agents useful
for calcium regulation (e.g., calcitonin, and parathyroid hormone);
antibacterial
agents (e.g., amikacin sulfate, aztreonam, chloramphenicol, chloramphenicol
palmitate, ciprofloxacin, clindamycin, clindamycin palmitate, clindamycin
phosphate, metronidazole, metronidazole hydrochloride, gentamicin sulfate,
lincomycin hydrochloride, tobramycin sulfate, vancomycin hydrochloride,
polymyxin B sulfate, colistimethate sodium, and colistin sulfate); antiviral
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CA 02576556 2007-02-01
agents (e.g., interferon alpha, beta or gamma, zidovudine, amantadine
hydrochloride, ribavirin, and acyclovir); antimicrobials (e.g., cephalosporins
such as cefazolin sodium, cephradine, cefaclor, cephapirin sodium,
ceftizoxime sodium, cefoperazone sodium, cefotetan disodium, cefuroxime e
azotil, cefotaxime sodium, cefadroxil monohydrate, cephalexin, cephalothin
sodium, cephalexin hydrochloride monohydrate, cefamandole nafate, cefoxitin
sodium, cefonicid sodium, ceforanide, ceftriaxone sodium, ceftazidime,
cefadroxil, cephradine, and cefuroxime sodium; penicillins such as ampicillin,
amoxicillin, penicillin G benzathine, cyclacillin, ampicillin sodium,
penicillin G
potassium, penicillin V potassium, piperacillin sodium, oxacillin sodium,
bacampicillin hydrochloride. cloxacillin sodium, ticarcillin disodium,
aziocillin
sodium, carbenicillin indanyl sodium, penicillin G procaine, methicillin
sodium,
and nafcillin sodium; erythromycins such as erythromycin ethylsuccinate,
erythromycin, erythromycin estolate, erythromycin lactobionate, erythromycin
stearate, and erythromycin ethylsuccinate; and tetracyclines such as
tetracycline hydrochloride, doxycycline hyclate, and minocycline
hydrochloride, azithromycin, clarithromycin) anti-infectives (e.g., GM-CSF);
bronchodilators (e.g., sympathomimetics such as epinephrine hydrochloride,
metaproterenol sulfate, terbutaline sulfate, isoetharine, isoetharine
mesylate,
isoetharine hydrochloride, albuterol sulfate, albuterol, bitolterolmesylate,
isoproterenol hydrochloride, terbutaline sulfate, epinephrine bitartrate,
metaproterenol sulfate, epinephrine, and epinephrine bitartrate;
anticholinergic agents such as ipratropium bromide; xanthines such as
aminophylline, dyphylline, metaproterenol sulfate, and aminophylline; mast
cell stabilizers such as cromolyn sodium; inhalant corticosteroids such as
beclomethasone dipropionate (BDP), and beclomethasone dipropionate
monohydrate; salbutamol; ipratropium bromide; budesonide; ketotifen;
salmeterol; xinafoate; terbutaline sulfate; triamcinolone; theophylline;
nedocromil sodium; metaproterenol sulfate; albuterol; flunisolide; fluticasone
proprionate, steroidal compounds and hormones (e.g., androgens such as
danazol, testosterone cypionate, fluoxymesterone, ethyltestosterone,
testosterone enathate, methyltestosterone, fluoxymesterone, and testosterone
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cypionate; estrogens such as estradiol, estropipate, and conjugated
estrogens; progestins such as methoxyprogesterone acetate, and
norethindrone acetate; corticosteroids such as triamcinolone, betamethasone,
betamethasone sodium phosphate, dexamethasone, dexamethasone sodium
phosphate, dexamethasone acetate prednisone, methylprednisolone acetate
suspension, triamcinolone acetonide, methylprednisolone, prednisolone
sodium phosphate, methylprednisolone sodium succinate, hydrocortisone
sodium succinate, triamcinolone hexacetonide, hydrocortisone,
hydrocortisone cypionate, prednisolone, fludrocortisone acetate,
paramethasone acetate, prednisolone tebutate, prednisolone acetate,
prednisolone sodium phosphate, and hydrocortisone sodium succinate; and
thyroid hormones such as levothyroxine sodium); hypoglycemic agents (e.g.,
human insulin, purified beef insulin, purified pork insulin, glyburide,
chlorpropamide, tolbutamide, and tolazamide); hypolipidemic agents (e.g.,
clofibrate, dextrothyroxine sodium, probucol, simvastatin, pravastatin,
atorvastatin, lovastatin, and niacin); proteins (e.g., DNase, alginase,
superoxide dismutase, and lipase); nucleic acids (e.g., sense or anti-sense
nucleic acids encoding any therapeutically useful protein, including any of
the
proteins described herein); agents useful for erythropoiesis stimulation
(e.g.,
erythropoietin); antiulcer/antireflux agents (e.g., famotidine, cimetidine,
and
ranitidine hydrochloride); antinauseants/antiemetics (e.g., meclizine
hydrochloride, nabilone, prochlorperazine, dimenhydrinate, promethazine
hydrochloride, thiethylperazine, and scopolamine); oil-soluble vitamins (e.g.,
vitamins A, D, E, K, and the like); as well as other drugs such as mitotane,
halonitrosoureas, anthrocyclines, and ellipticine.
A description of these and other classes of useful drugs and a listing of
species within each class can be found in Martindale, The Extra
Pharmacopoeia, 30th Ed. (The Pharmaceutical Press, London 1993).
Examples of other drugs useful in the compositions and methods
described herein include ceftriaxone, ceftazidime, oxaprozin, albuterol,
valacyclovir, urofollitropin, famciclovir, flutamide, enalapril, fosinopril,
acarbose, lorazepan, follitropin, fluoxetine, lisinopril, tramsdol,
levofloxacin,
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zafirlukast, interferon, growth hormone, interleukin, erythropoietin,
granulocyte
stimulating factor, nizatidine, perindopril, erbumine, adenosine, alendronate,
alprostadil, benazepril, betaxolol, bleomycin sulfate, dexfenfluramine,
fentanyl,
flecainid, gemcitabine, glatiramer acetate, granisetron, lamivudine,
mangafodipir trisodium, mesalamine, metoprolol fumarate, metronidazole,
miglitol, moexipril, monteleukast, octreotide acetate, olopatadine,
paricalcitol,
somatropin, sumatriptan succinate, tacrine, nabumetone, trovafloxacin,
dolasetron, zidovudine, finasteride, tobramycin, isradipine, tolcapone,
enoxaparin, fluconazole, terbinafine, pamidronate, didanosine, cisapride,
venlafaxine, troglitazone, fluvastatin, losartan, imiglucerase, donepezil,
olanzapine, valsartan, fexofenadine, calcitonin, and ipratropium bromide.
These drugs are generally considered to be water soluble.
Other drugs include albuterol, adapalene, doxazosin mesylate,
mometasone furoate, ursodiol, amphotericin, enalapril maleate, felodipine,
nefazodone hydrochloride, valrubicin, albendazole, conjugated estrogens,
medroxyprogesterone acetate, nicardipine hydrochloride, zolpidem tartrate,
amlodipine besylate, ethinyl estradiol, rubitecan, amlodipine
besylate/benazepril hydrochloride, paroxetine hydrochloride, paclitaxel,
atovaquone, felodipine, podofilox, paricalcitol, betamethasone dipropionate,
fentanyl, pramipexole dihydrochloride, Vitamin D3 and related analogues,
finasteride, quetiapine fumarate, alprostadil, candesartan, cilexetil,
fluconazole, ritonavir, busulfan, carbamazepine, flumazenil, risperidone,
carbidopa, levodopa, ganciclovir, saquinavir, amprenavir, carboplatin,
glyburide, sertraline hydrochloride, rofecoxib carvedilol,
halobetasolproprionate, sildenafil citrate, celecoxib, chlorthalidone,
imiquimod,
simvastatin, citalopram, ciprofloxacin, irinotecan hydrochloride,
sparfloxacin,
efavirenz, cisapride monohydrate, lansoprazole, tamsulosin hydrochloride,
mofafinil, clarithromycin, letrozole, terbinafine hydrochloride, rosiglitazone
maleate, lomefloxacin hydrochloride, tirofiban hydrochloride, telmisartan,
diazapam, loratadine, toremifene citrate, thalidomide, dinoprostone,
mefloquine hydrochloride, chloroquine, trandolapril, docetaxel, mitoxantrone
hydrochloride, tretinoin, etodolac, triamcinolone acetate, estradiol.
ursodiol,
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nelfinavir mesylate, indinavir, beclomethasone dipropionate, oxaprozin,
flutamide, famotidine, prednisone, cefuroxime, lorazepam, digoxin, lovastatin,
griseofulvin, naproxen, ibuprofen, isotretinoin, tamoxifen citrate,
nimodipine,
amiodarone, and alprazolam.
The drug delivery device of the present invention can be used for the
treatment of hypertension, angina, diabetes, HIV AIDS, pain, depression,
psychosis, microbial infections, gastro esophageal reflux disease, impotence,
cancer, cardiovascular diseases, gastric/stomach ulcers, blood disorders,
nausea, epilepsy, Parkinson's disease, obesity, malaria, gout, asthma,
erectile
dysfunction, impotence, urinary incontinence, irritable bowel syndrome,
ulcerative colitis, smoking, arthritis, rhinitis, Alzheimer's disease,
attention
deficit disorder, cystic fibrosis, anxiety, insomnia, headache, fungal
infection,
herpes, hyperglycemia, hyperlipidemia, hypotension, high cholesterol,
hypothyroidism, infection, inflammation, mania, menopause, multiple
sclerosis, osteoporosis, transplant rejection, schizophrenia, neurological
disorders.
Excipients may also be included in the composition or device of the
present invention. Excipients may be selected from diluents, compression
agents, extrusion agents, glidants, lubricants, solubilizers, wetting agents,
surfactants, penetration enhancers, pigments, colorants, flavoring agents,
sweetners, antioxidants, acidulants, stabilizers, antimicrobial preservatives
and binders.
These excipients may be chosen from:
(1) diluents such as microcrystalline cellulose, calcium phosphate,
mannitol, sorbitol, xylitol, glucitol, ducitol, inositiol, arabinitol;
arabitol,
galactitol, iditol, allitol, fructose, sorbose, glucose, xylose, trehalose, al
lose,
dextrose, altrose, gulose, idose, galactose, talose, ribose, arabinose,
xylose,
lyxose, sucrose, maltose, lactose, lactulose, fucose, rhamnose, melezitose,
maltotriose, and raffinose. Preferred sugars include mannitol, lactose,
sucrose, sorbitol, trehalose, glucose,
(2) surfactants, wetting agents and solubilisers such as glycerol
monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan
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CA 02576556 2013-03-20
esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as
cetomacrogol 1000), polyoxyethlylene castor oil derivatives, polyoxyethylene
sorbitan fatty acid esters (e.g., TVVEENTm), polyoxyethylene stearates, sodium
dodecylsulfate, TyloxapolTm (a nonionic liquid polymer of the alkyl aryl
polyether alcohol type, also known as superinone or triton) is another useful
solubilisers. Most of these solubilisers, wetting agents and surfactants are
known pharmaceutical excipients and are described in detail in the Handbook
of Pharmaceutical Excipients, published jointly by the American
Pharmaceutical Association and The Pharmaceutical Society of Great Britain
(The Pharmaceutical Press, 1986).
Preferred wetting agents include tyloxapol, poloxamers such as
PLURONICTM F68, F127, and F108, which are block copolymers of ethylene
oxide and propylene oxide, and polyxamines such as TETRONICTm 908 (also
known as POLOXAMINETm 908), which is a tetrafunctional block copolymer
derived from sequential addition of propylene oxide and ethylene oxide to
ethylenediamine (available from BASF), dextran, lecithin, dialkylesters of
sodium sulfosuccinic acid such as AEROSOLTM OT, which is a dioctyl ester of
sodium sulfosuccinic acid (available from American Cyanimid), DUPONOLTM
P, which is a sodium lauryl sulfate (available from DuPont), TRITONTm X-200,
which is an alkyl aryl polyether sulfonate (available from Rohm and Haas),
TWEENTm 20 and TWEENTNA 80, which are polyoxyethylene sorbitan fatty acid
esters (available from ICI Specialty Chemicals), CarbowaxTM 3550 and 934,
which are polyethylene glycols (available from Union Carbide), Crodesta TM F-
110, which is a mixture of sucrose stearate and sucrose distearate, and
Crodesta TM SL-40 (both available from Croda Inc.), and SA9OHCO, which is
Cg18H37-CH2 (CON(CH3)CH2(CHOH)4 CF20F1)2.
Wetting agents which have been found to be particularly useful include
TetronicTm 908, the Tweens, Pluronic F-68 and polyvinylpyrrolidone. Other
useful wetting agents include decanoyl-N-methylglucamide; n-decyl-.beta.-D-
glucopyranoside; n-decyl-.beta.-D-maltopyranoside; n-dodecyl-.beta.-D-
glucopyranoside; n-dodecyl.beta.-D-maltoside; heptanoyl-N-methylglucamide;
n-heptyl-.beta.-D-glucopyranoside; n-heptyl-.beta.-D-thioglucoside; n-hexyl
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.beta.-D-glucopyranoside; nonanoyl-N-methylglucamide; n-octyl-.beta.-D-
glucopyranoside; octanoyl-N-methylglucamide; n-octyl-.beta.-D-
glucopyranoside; and octyl-.beta.-D-thioglucopyranoside. Another preferred
wetting agent is p-isononylphenoxypoly(glycidol), also known as Olin-1OG or
Surfactant 10-G (commercially available as 10G from Olin Chemicals). Two or
more wetting agents can be used in combination.
The pharmaceutical composition or device may further include a
pegylated excipient. Such pegylated excipients include, but are not limited
to,
pegylated phospholipids, pegylated proteins, pegylated peptides, pegylated
sugars, pegylated polysaccharides, pegylated block-co-polymers with one of
the blocks being PEG, and pegylated hydrophobic compounds such as
pegylated cholesterol. Representative examples of pegylated phospholipids
include 1,2-diacyl 1-sn-glycero-3-phosphoethanolamine-N-[Poly(ethylene
glycol) 2000] ("PEG 2000 PE") and 1,2-diacyl-sn-glycero-3-
phosphoethanolamine-N-[- Poly(ethylene glycol) 5000]("PEG 5000 PE"),
where the acyl group is selected, for example, from dimyristoyl, dipalmitoyl,
distearoyl, diolcoyl, and 1-palmitoyI-2-oleoyl.
One skilled in the art can select appropriate excipients for use in the
composition of the present invention.
In an embodiment, the device is coated with a non-disintegrating and
non-semi-permeable coat. Materials useful for forming the non-disintegrating
non-semi-permeable coat are ethylcellulose, polymethylmethacrylates,
methacrylic acid copolymers and mixtures thereof.
In yet another embodiment, the device is coated with a non-
disintegrating semipermeable coat. Materials useful for forming the non-
disintegrating semipermeable coat are cellulose esters, cellulose diesters,
cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose
acylate,
cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose
diacetate,
cellulose triacetate, cellulose acetate propionate, and cellulose acetate
butyrate. Other suitable polymers are described in U.S. Pat. Nos. 3,845,770,
3,916,899, 4,008,719, 4,036,228 and 4,612,008. The most preferred non-
disintegrating semipermeable coating material is cellulose acetate comprising
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CA 02576556 2007-02-01
an acetyl content of 39.3 to 40.3%, commercially available from Eastman Fine
Chemicals.
In an alternative embodiment, the non-disintegrating semipermeable or
non-disintegrating non-semi-permeable coat can be formed from the above-
described polymers and materials that will form passage ways in the coat.
The passage way forming agents dissolve on contact with fluid and form
passages through which fluid and active pharmaceutical ingredient(s) can
move through the coat. The passage way forming agent can be a water
soluble material or an enteric material. Some examples of the preferred
materials are sodium chloride, potassium chloride, sucrose, sorbitol,
mannitol,
polyethylene glycol (PEG), polyvinyl pyrolidone, propylene glycol,
hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl
methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols,
methacrylic acid copolymers and mixtures thereof. The preferred passage
way forming agent is PEG 600, polyvinyl pyrolidone and hydroxypropyl
methycellulose.
The active pharmaceutical ingredient(s) that are water soluble or that
are soluble under intestinal conditions may also be used to create passage
ways in the coat.
The passage way creating agent comprises approximately 0 to about
75% of the total weight of the coating, most preferably about 0.5% to about
25% of the total weight of the coating. The passage way creating agent
dissolves or leaches from the coat to form passage ways in the coat for the
fluid to enter the core and dissolve the active ingredient.
The coat may also be formed with commonly known excipients such as
plasticizers and anti-tacking agents. Some commonly known plasticizers
include adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate,
triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid
esters, and
those described in the Encyclopedia of Polymer Science and Technology, Vol.
10 (1969), published by John Wiley & Sons. The preferred plasticizers are
triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil,
acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol,
diethyloxalate,
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diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate,
dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate,
glyceroltributyrate, and the like. Depending on the particular plasticizer,
amounts of from 0 to about 25%, and preferably about 2% to about 20% of
the plasticizer can be used based upon the total weight of the coating
polymer. The preferred anti tacking agent is talc. Depending on the coating
polymer, amounts of from 0 to about 70%, and preferably about 10% to about
50% of talc can be used based upon the total weight of the coating polymer.
As used herein the term passageway includes an aperture, orifice,
bore, hole, weaken area or as created by soluble or leachable materials
Generally, the coat around the device will comprise from about 0.5% to
about 70% and preferably about 0.5% to about 50% based on the total weight
of the device with the coating.
In an alternative embodiment, the dosage form of the device may also
comprise an effective amount of the active pharmaceutical ingredient that is
available for immediate release as a loading dose. This may be coated onto
the coat of the device or it may be incorporated into the coat or it may be
press coated into the coated device.
In the preparation of coated device, various conventional well known
solvents may be used to prepare the device and apply the external coating to
the device. In addition, various diluents, excipients, lubricants, dyes,
pigments, dispersants etc. which are disclosed in Remington's
Pharmaceutical Sciences, 1995 Edition may be used in the device.
The above disclosure generally describes the present invention. A
more complete understanding can be obtained by reference to the following
specific Examples. The Examples are described solely for purposes of
illustration and are not intended to limit the scope of the invention. Changes
in form and substitution of equivalents are contemplated as circumstances
may suggest or render expedient. Although specific terms have been
employed herein, such terms are intended in a descriptive sense and not for
purposes of limitation.
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EXAMPLE 1
A controlled release tablet containing metoprolol succinate and having
the following formula is prepared as follows:
% by weight
Metoprolol Succinate 20
Trehalose 20
Silicone dioxide 1
Crospovidone 20
Xanthan gum 20
Lactose 18
Magnesium stearate 1
(a) Granulation
The metoprolol succinate, trehalose, silicone dioxide, crospovidone,
lactose and xanthan is added to fluid bed granulator with a top spray
assembly. This is granulated by spraying a 1% binding solution of polyvinyl
pyrolidone. Once the binding solution is depleted, the granules are dried in
the granulator until the loss on drying is less than 5%. The dried granules
are
passed through a Comil.
(b) Tableting
The magnesium stearate is blended with the granules in a V-blender.
After blending, the granules are compressed to tablets on a rotary press.
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EXAMPLE 2
A controlled release tablet containing venlafaxine hydrochloride and
having the following formula is prepared as follows:
% by weight
Venlafaxine hydrochloride 20
Trehalose 30
Silicone dioxide 1
Crospovidone 20
Xanthan gum 20
Ethycellulose 10
Lactose 8
Magnesium stearate 1
(a) Granulation
The venlafaxine hydrochloride, trehalose, silicone dioxide,
crospovidone, lactose, ethylcellulose and xanthan is added to high shear
granulator. This is granulated using isopropyl alcohol. The granules are dried
in a fluid bed dryer until the loss on drying is less than 5%. The dried
granules are passed through a Comil.
(b) Tableting
The magnesium stearate is blended with the granules in a V-blender.
After blending, the granules are compressed to caplets on a rotary press.
(c) Curing
The tablets are cured by exposing them to a temperature of 40 C and
relative humidity of 70% for 3 months.
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EXAMPLE 3
A controlled release tablet containing divalproex sodium and having the
following formula is prepared as follows:
% by weight
Divalproex sodium 20
Trehalose 5
Silicone dioxide 1
Sodium starch glycolate 30
Hydroxypropyl methyl cellulose 20
Hydrogenated castor oil 2
Lactose 20
Magnesium stearate 1
(a) Preparation by Wet Granulation
Divalproex Na, trehalose, silicone dioxide, sodium starch glycolate,
hydroxypropylmethyl cellulose and lactose is granulated in a Hobart low shear
mixer using an alcoholic solution of castor oil. The wet granules are dried in
a
tray dryer oven. The dried granules are lubricated with magnesium stearate
in a V-blender.
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CA 02576556 2007-02-01
,
,
EXAMPLE 4
A controlled release tablet containing Nisoldipine and having the
following formula is prepared as follows:
% by weight
Nisoldipine 10
Trehalose 10
Silicone dioxide 0.5
Croscarmelose Na 40
Hydroxyethyl cellulose 25
Lactose 10
Sodium lauryl sulphate 9
Magnesium stearate 0.5
Preparation by Direct Compression
Nisoldipine, silicone dioxide, lactose, hydroxyethyl cellulose, trehalose
and sodium laury sulphate is dry blended in a high shear granulator.
Magnesium stearate is added to the dry blend in a V-blender.
After blending, the dry blended granules from (a) are compressed into
tablets.
EXAMPLE 5
A controlled release tablet containing Paroxetine HCI and having the
following formula is prepared as follows:
% by weight
Paroxetine HCI 20
Trehalose 19
Silicone dioxide 0.5
Crospovidone 40
Hydroxypropyl ethyl cellulose 10
Xanthum gum 10
Magnesium stearate 0.5
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Preparation by Direct Compression
Crospovidone, silicone dioxide, trehalose, paroxetine hydrochloride,
hydroxypropylmethyl cellulose, and xanthan gum is dry blended in a Hobart
low shear mixer. Magnesium stearate is added to the dry blend in a V-
blender. After blending, the dry blended granules from are compressed into
tablets.
EXAMPLE 6
A controlled release pellets consisting of extruded spheroids containing
venlafaxine HCI and having the following formula is prepared as follows:
% by weight
Carbedilol HCI 3
Trehalose 50
Crospovidone 20
Microcrystalline cellulose 13
Polysorbate 80 3
Glyceryl monooleate 3
Xanthan gum 8
(a) Preparation of Extrudate and Spheroids
Venlafaxine HCI, trehalose, crospovidone, xcipie gum and
microcrystalline cellulose is wet granulated in a Hobart low shear mixer. The
wet mass is extruded and spheronized.
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EXAMPLE 7
Preparation of controlled release excipients for use as a direct
compressible premanufactured excipients to be used for controlling the
release of active pharmaceutical ingredients
% by weight
Crospovidone 30
Trehalose 20
Silicone dioxide 1
Hydroxypropyl methylcellulose 10
Xanthan gum 10
Ethylcellulose 9
Lactose 20
The materials are dry blended in a v-blender.
EXAMPLE 8
Optional coating systems that may be used to coat products from
examples 1 to 6 are as follows:
1. Non-disintegrating non-semi-permeable Coat type 1
% by weight
EudragitTM NE 30 D 41.7
Talc 12.5
Antifoam agent 0.1
Water 45.7
Talc is added to water to which antifoaming agent has been added
while stirring with a high shear mixer. The mixture is added slowly to
Eudragit
NE 30 D solution and stirred. The coating solution is then sprayed onto the
tablets or to a theoretical weight gain of about 5% to 50 wt%.
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2. Using non-disintegrating non-semi-permeable Coat type 2
% by weight
Ethylcellulose 80
Hydroxypropylmethylcellulose 20
This is made as a solution in acetone. The coating solution is then
sprayed onto the tablets or pellets to a theoretical weight gain of about 2%
to
about 15 wtcYo.
3. Non disintegrating non semi-permeable Coat type 3
`)/0 by weight
Eudragit RL 30 D 46.3
Triethyl citrate 2.8
Silicone dioxide 4.2
Antifoam agent 0.1
Water 46.6
Silicone dioxide is added to water to which antifoaming agent and
triethyl citrate has been added while stirring with a high shear mixer. The
mixture is added slowly to Eudragit RL 30 D solution and stirred. The coating
solution is then sprayed onto the tablets or pellets to a theoretical weight
gain
of about 3% to about 20 wt%.
4. Non-disintegrating non-semi-permeable Coat type 4
% by weight
Eudragit RL 30 D/Eudragit RS 30 D (1:9) 46.3
Triethyl citrate 2.8
Silicon dioxide 4.2
Antifoam agent 0.1
Water 46.6
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Silicone dioxide is added to water to which antifoaming agent and
triethyl citrate has been added while stirring with a high shear mixer. The
mixture is added slowly to a mixture of Eudragit RL 30 D and RS 30 D
solution and stirred. The coating solution is then sprayed onto the tablets
and
pellets to a theoretical weight gain of about 3% to about 15 wt%.
5. Using non disintegrating semi-permeable Coat type 1
% by weight
Cellulose acetate 80
Triacetin 5
PEG 600 14.5
Red Iron oxide 0.5
The cellulose acetate is dissolved in acetone while stirring with a high
shear mixer. The red iron oxide, polyethylene glycol 600 and triacetin are
added to the cellulose acetate solution and stirred until a clear solution is
obtained. The clear coating solution is then sprayed onto the tablets or
pellets
to a theoretical weight gain of about 1 /0 to about 15 wt%.
6. Using disintegrating coat type 1
The tablets or pellets may be coated with an OpadryTM or
LustreClearTM material or other suitable water-soluble material by first
dissolving the opadry material, preferably Opadry Clear, in purified water.
The Opadry solution is then sprayed onto the tablets or pellets to a
theoretical
coating level of about 2% to about 15 wt%.
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7. Using disintegrating coat type 2
% by weight
Eudragit L 30 D 46.3
Polyethylene glycol 600 2.8
Talc 7.0
Antifoam agent 0.1
Water 50.8
Talc is added to water to which antifoaming agent and polyethylene
glycol 600 has been added while stirring with a high shear mixer. The mixture
is added slowly to a mixture of Eudragit L 30 D solution and stirred. The
coating solution is then sprayed onto the tablets and pellets to a theoretical
weight gain of about 3% to about 15 wt%.
8. Using disintegrating coat type 2
% by weight
Eudragit L and/or Eudragit S 10.0
Polyethylene glycol 600 2.0
Talc 5.0
Antifoam agent 0.1
Water 5.0
Ethanol 77.9
Talc is added to ethanol and water to which antifoaming agent and
polyethylene glycol 600 has been added while stirring with a high shear mixer.
The mixture is added slowly to a mixture of Eudragit L and or Eudragit S in
Ethanol and stirred. The coating solution is then sprayed onto the tablets and
pellets to a theoretical weight gain of about 3% to about 20 wt%.
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