Note: Descriptions are shown in the official language in which they were submitted.
CA 02444814 2008-01-14
PHARMACEUTICAL DOSAGE FORM WITH
MULTIPLE COATINGS FOR REDUCED IMPACT OF
COATING FRACTURES
TECHNICAL FIELD
The present invention relates to novel unit dosage forms comprising
therapeutic
agents with improved resistance to coating fractures during processing,
manufacturing or
packaging.
BACKGROUND OF THE INVENTION
A number of prior art references teaches the advantages of delivery of
therapeutic
agents to the lower part of the gastrointestinal tract, especially the large
intestine or the colon.
These reference illustrate the difficulty of formulating dosage forms that
will achieve this
delivery benefit. For example, US Patent No. 5,541,170 and 5,541,171, Rhodes
et al., both
issued July 30, 1996, discuss the delivery of pharmacologically active agents,
especially 5-
aminosalicylic acid, to the large intestine for the treatment of colonic or
rectal disorders. US
Patent No. 5,686,105, Kelm et al., issued November 11, 1997, teaches colonic
delivery of
therapeutic agents wherein the dosage form comprises a coating system with at
least one
inner coating layer and one outer coating layer. The inner coating layer is an
enteric polymer
that begins to dissolve in an aqueous media at a pH between about 5 to about
6.3, and the
outer coating layer is an enteric polymer that begins to dissolve in an
aqueous media at a pH
of between about 6.8 to 7.2. US Patent No. 5,171,580, Iamartino et al., issued
Dec. 15, 1992,
teaches pharmaceutical preparations containing an active ingredient to be
released in the
lower part of the gastrointestinal tract, the large intestine and especially
the colon, consisting
of a core with the active, the core being coated with three protective layers
at different
solubilities. This reference focuses on providing more specific and reliable
release of a
therapeutic active agent to the lower part of the gastrointestinal tract,
especially the colon,
achieved with the three protection layers, as well as the benefits of having a
selective effect in
the colon. Other prior art references also focus on the benefits of delivering
therapeutic
agents to the colon. These references include US Patent Nos. 5,686,106, Kelm
et al., issued
Nov. 11, 1997; 5,914,132, Kelm et al., issued June 22, 1999; 4,910,021, Davis
et al., issued
CA 02444814 2008-01-14
March 20, 1990; 4,432,966, Zeitoun et al., issued Feb. 21, 1984; 5,654,004,
Okayama et al.,
issued August 5, 1997; 5,900,252, Calcanchi et al., issued May 4, 1999;
5,482,718, Shah et
al., issued Jan. 9, 1996; 5,316,772, Jurgens et al., issued May 31, 1994; EP
225,189, Davies,
et al., published June 10, 1987; and Khan et al., Drug Development and
Industrial Pharmacy,
26(5), 549-554 (2000).
None of the above prior art references, however, discusses the problem or
possibility
of coating fractures that may occur during processing, manufacturing, or
packaging of the
oral unit dosage form. Coating fractures may cause unreliable or inconsistent
delivery or
release of the therapeutic agent to the desired region of the gastrointestinal
tract. These
fractures may be associated with premature rupture or release of the unit
dosage forms.
Indeed, coating fractures may especially be problematic for larger than
average size unit
dosage forms or heavier unit dosage forms resulting from using larger
dosages/levels of the
therapeutic active.
The present invention, therefore, relates to solid unit dosage forms for oral
administration in humans or lower animals which minimizes the impact or
negative effects of
coating fractures, especially for larger or heavier unit dosage forms. By
reducing these
negative effects, these compositions maintain the desired site of delivery of
the therapeutic
agents in the gastrointestinal tract.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition in a solid unit
dosage
form for oral administration in a human or lower animal comprising:
a. a safe and effective amount of a therapeutically active agent;
b. an inner coating layer selected from the group consisting of
poly(methacrylic
acid, methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate)
1:1, and mixtures thereof; and
c. an outer coating layer comprising an enteric polymer or film coating
material;
wherein the inner coating layer is not the same as the outer coating layer;
wherein if the inner
coating layer is poly(methacrylic acid, methyl methacrylate) 1:1 then the
outer coating layer
is not poly(methacrylic acid, methyl methacrylate) 1:2 or is not a mixture of
poly(methacrylic
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CA 02444814 2008-01-14
acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate)
1:2; and
wherein the inner coating layer and the outer coating layer contain no
therapeutically active
agent.
In another embodiment the present invention relates to a pharmaceutical
composition
in a solid unit dosage form for oral administration in a human or lower animal
comprising:
a. a safe and effective amount of a therapeutically active agent;
b. an inner coating layer comprising poly(methacrylic acid, methyl
methacrylate)
1:2; and
c. an outer coating layer comprising an enteric polymer or film coating
material;
wherein the inner coating layer is not the same as the outer layer coating.
This invention
further relates to a method of maintaining the desired site of delivery of a
therapeutic agent in
the gastrointestinal tract by reducing the impact of coating fractures,
through administering
the above compositions to a human or lower animal.
DETAILED DESCRIPTION OF THE INVENTION
The phrase "safe and effective amount", as used herein, means an amount of
therapeutically active agent or other component of the present compositions,
high enough to
provide a significant positive modification of the condition to be treated,
but low enough to
avoid serious side effects (at a reasonable benefit/risk ratio), within the
scope of sound
medical judgment. A safe and effective amount of therapeutically active agent
or other
component of the present compositions, will vary with the particular condition
being treated,
the age and physical condition of the patient being treated, the severity of
the condition, the
duration of the treatment, the nature of concurrent therapy, the agent
selected and like factors.
Therapeutically Active Agent
The methods and compositions of the present invention comprise a safe and
effective
amount of the therapeutically active agent. In one embodiment the therapeutic
agents
suitable for incorporation into dosage forms of the present invention are
those for which
treatment of the colon is therapeutically advantageous. These include
therapeutic agents
useful for the treatment of diseases of the colon such as constipation,
diarrhea, irritable bowel
syndrome (IBS), Crohn's disease, colitis, ulcerative colitis, carcinomas,
idiopathic protitis,
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infection in which systemic absorption of the therapeutic agent is neither
required or desired,
and other diseases or disorders of the colon or rectum. These include actives
for constipation
and laxatives such as picosulfate and sennasides, anti-diarrheals such as
loperamide,
nonsteroidal anti-inflammatory drugs such as salicylates, indomethacin,
ibuprofen,
flurbiprofen, naproxen, piroxicam 5-amino salicylic acid (or pharmaceutically
acceptable
salts or esters thereof), balsalazide as well as agents disclosed in US
4,412,992, Chan, issued
Nov. 1, 1983, as well as NSAIDS disclosed in US 4,552,899, Sunshine et al.,
issued Nov. 12,
1985, steroids such as hydrocortisone, prednisone, prednisolone, prednisolone
phosphate,
prednisolone metasulpho-benzoate sodium, prednisolone sodium phosphate,
beclomethasone
dipropionate and beclomethasone valerate, glucocorticoids such as
dextramethazone,
antimicrobials or antiparasitic agents, (especially those effective against
anaerobic microbes
such as methotrexate), 5-aminosalicylic compounds, 4-aminosalicylic compounds,
sulfasalazine, benzalazine, erythromycin, chloroguine, iodochlorhydroxyquin,
disodohydroxyquin, neomycin and tetracyclines, immunosupressants such as
cyclosporine A,
chemotherapeutics or anti-cancer drugs for treatment of carcinomas,
gastrointestinal
stimulants and prokinetic agents such as cisapride, peppermint oil and other
carminative
essential oils, actives for the removal of excess bile acids such as
cholestyramine.
Certain therapeutic agents, particularly peptides and proteins, are subject to
lumenal
degradation in the stomach and small intestine. The colon may be a preferable
site of
absorption for such compounds since lumenal enzymatic activity is less in the
colon (M.
Mackay and E. Tomlinson, in Colonic Drug Absorption and Metabolism, P. R.
Bieck, ed.,
Marcel Dekker, Inc., New York, Basel, Hong Kong, 137-158 (1993)). Peptides and
proteins
that may exhibit improved systemic bioavailability benefit when released in
the colon include
calcitonin, insulin, and human growth hormone. In certain cases, the peptide
or protein may
be formulated with a system that enhances the absorption of the macromolecule
(M. Mackay
and E. Tomlinson, in Colonic Drug Absorption and Metabolism, P. R. Bieck, ed.,
Marcel
Dekker, Inc., New York, Basel, Hong Kong, 137-158 (1993)).
The therapeutically active agents are present in the solid dosage forms in
suitable unit
dosage amounts. These amounts will be known by those skilled in the art. In
one
embodiment the active agent is 5-amino salicylic acid or pharmaceutically
acceptable salts or
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esters thereof at a dosage range of from about 400 mg to about 1.5 grams per
tablet, in
another embodiment is from about 700 mg to about 900 mg per tablet.
The therapeutically active agent may be incorporated into one of the several
substrates
described herein in a manner consistent with the physical chemical properties
of the drug and
its pharmacodynamics, using techniques known to those skilled in the art.
The Inner and Outer Coating Layers
In one embodiment the coating layers of the present invention do not contain
any
therapeutically active agent of the present invention. In addition, the
"coating layers"
described herein refer to completely encasing or coating all of the solid unit
dosage form
(does not include coated microcrystal spheres, coated pellets, coated beads,
coated
microparticles or particles, or coated granules, of the therapeutically active
agent).
Inner Coating Layer
The inner coating layer is selected from the group consisting of
poly(methacrylic acid,
methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:1, and
mixtures
thereof. Generally the inner coating layer is selected based on the preferred
delivery site
desired and is applied to the core of the unit dosage form to achieve a
minimum coating
thickness from about 20 m to about 120 m. The coating thickness depends on
the actual
size of the unit dosage form, but in one embodiment the minimum coating
thickness of the
inner coating layer is from about 20 m to about 50 m.
In one embodiment the inner coating layer comprises poly(methacrylic acid,
methyl
methacrylate) 1:2, (Eudragit0 S), or other enteric polymer material which has
the same pH
release characteristics in aqueous media as Eudragit0 S. Eudragit0 S, an
anionic copolymer
derived from methacrylic acid and methyl methacrylate, with a ratio of free
carboxyl groups
to the ester groups of approximately 1:2, and a mean molecular weight of
approximately
135,000, from Rohm Tech. In one embodiment the inner coating layer is any
other polymer
with the same aqueous pH release characteristics as Eudragit0 S.
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Outer Coating LaYer
The outer coating layer comprises an enteric polymer or film coating material,
wherein the inner coating layer is not the same as the outer coating layer.
Generally, if the
inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:1
(Eudragit L) then the
outer coating layer is not poly(methacrylic acid, methyl methacrylate) 1:2
(Eudragit(& S) or is
not a mixture of poly(methacrylic acid, methyl methacrylate) 1:1 and
poly(methacrylic acid,
methyl methacrylate) 1:2. The outer coating material can be any coating
material that
protects the inner coating layer from fractures during handling and that
dissolves or is
removed in the gastrointestinal tract prior to the inner coating layer. The
outer coating layer
is either a single coating or multiple coatings of either an enteric polymer
material or film
coating material. In another embodiment the unit dosage form has a single
outer coating
layer. In another embodiment the outer coating layer is an anionic copolymer.
In one
embodiment the outer coating cannot comprise an enteric polymer or mixtures
thereof with
the same pH of release in aqueous media as Eudragit S. If the. inner coating
is
poly(methacrylic acid, methyl methacrylate 1:2, then the outer coating layer
can only
comprise poly(methacrylic acid, methyl methacrylate 1:2 (Eudragit0 S) if it is
mixed with
another enteric polymer or film coating material such that the pH of release,
in aqueous
media, for the mixture is less than the pH of release (aqueous media) for
poly(methacrylic
acid, methyl methacrylate 1:2 (Eudragit S) alone.
In another embodiment the outer coating layer is an enteric polymer material
that
begins to dissolve in an aqueous media at a pH of less than about 7, in
another embodiment at
a pH of less than about 6.8. Generally the outer coating layer is applied to
the core of the unit
dosage form to achieve a minimum thickness of from about 10 m to about 200
m, in
another embodiment is from about 30 m to about 150 m.
In one embodiment the outer coating layer is selected from the group
consisting of
film coatings, cellulose derivatives, cellulose ethers, methyl cellulose,
ethylcellulose,
carboxymethylcellulose, carboxymethylethylcellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, low viscosity
hydroxypropyl
cellulose, low viscosity hydroxypropyl methylcellulose, wax or wax like
substance, such as
carnauba wax, fatty alcohols, hydrogenated vegetable oils, zein, shellac,
sucrose, Arabic gum,
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polyethylene glycol, polyvinylpyrolidone, gelatin, sodium alginate, dextrin,
psyllium husk
powder, polymethacrylates, anionic polymethacrylates, poly(methacrylic acid,
methyl
methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2
and
poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate,
cellulose acetate
trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose
propionate
phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate,
hydroxypropyl
methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose
hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl
acrylate) 1:1,
and compatible mixtures thereof.
In another embodiment the outer coating layer is selected from the group
consisting of
cellulose derivatives, cellulose ethers, methyl cellulose, ethylcellulose,
carboxymethylce11u1ose, carboxymethylethylcellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, low viscosity
hydroxypropyl
cellulose, low viscosity hydroxypropyl methylcellulose, fatty alcohols,
hydrogenated
vegetable oils, zein, shellac, sucrose, Arabic gum, polyethylene glycol,
polyvinylpyrolidone,
gelatin, sodium alginate, dextrin, psyllium husk powder, polymethacrylates,
anionic
polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures
of
poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid,
methyl
methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate,
hydroxypropyl
methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose
acetate
maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate
succinate
(HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate
phthalate,
poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.
In another embodiment the outer coating layer is selected from the group
consisting of
anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1,
mixtures of
poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid,
methyl
methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate,
hydroxypropyl
methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose
acetate
maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate
succinate
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(HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate
phthalate,
poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.
In another embodiment the outer coating layer is a single layer of a mixture
of
poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit L) and
poly(methacrylic acid,
methyl methacrylate) 1:2 (Eudragit S) in a ratio of about 1:10 to about 1:10,
preferably
about 1:5 to about 1:3 more preferably about 2:3. The coating thickness
depends on the
actual size of the unit dosage form, but in one embodiment the minimum coating
thickness of
the outer coating layer is from about 10 m to about 50 m, in another
embodiment is from
about 20 m to about 40 m.
In another embodiment the outer coating layer is a single coating of an
enteric
polymer that begins to dissolve in aqueous media at a pH between about 5 to
about 6.3, in
another embodiment at a pH between about 5 to about 6, in even another
embodiment at a pH
between about 5 to about 5.5.
In one embodiment, the function of the outer coating layer is to prevent or
minimize
fractures of the inner coating layer during formulation processing,
manufacturing, and
packaging, and the function of the inner coating layer is to maintain the
desired point of
release of the therapeutic active agent in the gastrointestinal tract. For
example if the inner
coating is poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit S), the
present
invention maintains the desired point of release, as described, for example,
in US Patent Nos.
5,541,170 and 5,541,171, Rhodes et al.
In one embodiment the total coating thickness (both the inner and outer
coating layers
together) is from about 5 mg/cm2 to about 40 mg/cm 2, in another embodiment is
from about
10 mg/cm2 to about 15 mg/cm2.
Specific examples of the outer coating layer follow.
Eudragit L, is an anionic copolymer derived from methacrylic acid and methyl
methacrylate, with a ratio of free carboxyl groups to the ester groups of
approximately 1:1,
and a mean molecular weight of approximately 135,000, from Rohm Tech;
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Eudragit L 30 D, is an aqueous acrylic resin dispersion, an anionic copolymer
derived from
methacrylic acid and ethyl acrylate with a ratio of free carboxyl groups to
the ester groups of
approximately 1:1, and a mean molecular weight of approximately 250,000; (it
is supplied as
an aqueous dispersion containing 30% w/w of dry lacquer substance);
Eudragit L 100-55, is an anionic copolymer derived from methacrylic acid and
ethyl
acrylate, with a ratio of free carboxyl groups to the ester groups of
approximately 1:1, and a
mean molecular weight greater than about 100,000;
cellulose acetate phthalate or CAP , available from Eastman Chemical;
cellulose acetate trimelliate, CAT available from Eastman Chemical;
hydroxypropyl methylcellulose phthalate (USP/NF type 220824) HPMCP 50 and
(USP/NF
type 200731) HPMCP 55 available from Shin Etsu Chemical;
polyvinyl acetate phthalate, PVAP , available from Colorcon;
hydroxypropyl methylcellulose acetate succinate, HPMCAS , available from Shin
Etsu
Chemical; hydroxypropylcellulose, Klucel .
To enhance the elasticity of the coating materials, preferably the coating
material of
the present invention also comprises a plasticizer. Appropriate plasticizers
include
polyethylene glycols, propylene glycols, 1,2-propylene glycol, dibutyl
phthalate, diethyl
phthalate, tributyl citrate, tributyrin, butyl phthalyl butyl glycolate
(Santicizer B-16, from
Monsanto, St. Louis, Missouri), triacetin, castor oil and citric acid esters;
in another
embodiment the plasticizer is dibutyl phthalate, tributyl citrate, or triethyl
citrate. These
plasticizers are present in an amount to facilitate the coating process and to
obtain an even
coating film with enhanced physical stability. Generally the coating material
comprises from
about 0% to about 50% of a plasticizer, preferably from about 2% to about 25%
by weight,
more preferably from about 10% to about 20% by weight of the enteric polymer.
In addition, to facilitate the coating process, the coating material may also
comprise
inert solid particulates. Preferred inert solid particulates include talc and
titanium dioxide.
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The selections of optional plasticizer, optional inert solid particulate, and
levels
thereof, coating formulation type (solvent, ammoniated aqueous solution, or
aqueous
dispersion), and process are based upon the specific enteric polymer or film
coatings used
and the type of dosage form used according to criteria known to those skilled
in the art. The
solvent for the coating layers may be organic or aqueous. In one embodiment
the coating
layer is obtained via the use of an aqueous dispersion of the coating
material.
The Dosage Form and Method of Making the Dosage Form
A safe and effective amount of therapeutically active agent is incorporated
into a solid
unit dosage form. The term "solid unit dosage form" means any dosage form,
preferably non-
liquid, intended to be swallowed and having a sufficiently defined form to be
coated. Solid
unit dosage forrns may be selected from the group consisting of a hard or soft
capsule or a
compressed tablet. In one embodiment the solid dosage forms of the present
invention are
selected from the group consisting of soft gelatin capsules; hard gelatin
capsules; and
compressed tablets of any size or shape. In one embodiment the unit dosage
form of the
present invention comprises a unit dosage form from about 550 mg to about 1.5
gram total
weight, in another embodiment from about 600 mg to about 1.2 grams total
weight, and in
even another embodiment from about 750 mg to about 1 gram total weight.
In one embodiment the unit dosage form is a spherical or elliptical soft
elastic gelatin
capsule. The soft elastic gelatin capsule is filled with therapeutically
active agent suspended
in a suitable vehicle compatible with the soft gelatin capsule.
In still another embodiment the unit dosage form is a hard capsule (i.e.
starch or
gelatin hard capsule), for example a starch capsule such as Capill from
Capsulgel
(Greenwood, SC) in which the length of the long axis of the capsule is less
than about 10 mm
and not more than about 1.5 times greater than the short axis diameter of the
capsule. The
capsule may be filled with a solid form of therapeutically active agent as
described above, or
alternatively with therapeutically active agent dissolved or suspended in a
suitable vehicle
compatible with the capsule wall.
CA 02444814 2008-01-14
In another embodiment the unit dosage form is a compressed spherical or
elliptical
tablet. The tablet is comprised of a solid form of therapeutically active
agent and is
compressed using conventional equipment and processes.
In addition to the therapeutically active agent the compositions of this
invention also
generally comprise pharmaceutically acceptable excipients. As used herein,
"excipient"
means one or more compatible solid or liquid filler diluents or encapsulating
substances
which are suitable for administration to a subject. The term "compatible", as
used herein,
means that the components of the composition are capable of being commingled
with the
active agent, and with each other, in a manner such that there is no
interaction which would
substantially reduce the pharmaceutical efficacy of the composition under
ordinary use
situations. Pharmaceutically-acceptable excipients must, of course, be of
sufficiently high
purity and sufficiently low toxicity to render them suitable for
administration to the subject
being treated. Excipients may act to facilitate incorporation of the
therapeutically active
agent into the dosage form, modify the release of the therapeutically active
agent from the
dosage form, stabilize the therapeutically active agent, or enhance absorption
of the
therapeutically active agent. Excipients should be safe for their intended use
at the levels
employed in the formulation. The formulation of therapeutically active agent
and excipients
is selected according to criteria well known to those skilled in the art to
achieve the desired
release rate, stability, absorption, and to facilitate the dosage form
manufacture.
Some examples of pharmaceutically-acceptable excipients or components thereof
are
sugars, such as lactose, glucose, and sucrose; starches, such as cornstarch,
potato starch, and
sodium starch glycolate at a level of about 1% to about 8% by weight, in
another embodiment
from about 2% to about 4% by weight; cellulose and its derivatives, such as
sodium
carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered
tragacanth; malt;
gelatin; talc; solid lubricants, such as stearic acid, magnesium stearate; or
calcium sulfate;
vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil,
corn oil, and oil of
theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and
polyethylene
glycol; alginic acid; emulsifiers, such as the Tweens ; wetting agents such as
sodium lauryl
sulfate; coloring agents; flavoring agents; excipients; tableting agents;
stabilizers;
antioxidants; preservatives; pyrogen-free water; isotonic saline; and
phosphate buffer
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solutions. Excipients are described in Remington's Pharmaceutical Sciences,
Mack
Publishing Co. (19th edit. 1995); Modern Pharmaceutics, Vol. 7, Chapters 9 &
10, Banker &
Rhodes (1979); Lieberman, et al, Pharmaceutical Dosage Forms: Tablets (1981);
and Ansel,
Introduction to Pharmaceutical Dosage Forms, 2d (1976). Their selection will
depend on
secondary considerations like taste, cost, and shelf stability, etc. which are
not critical for the
purposes of the subject invention, and can be made without difficulty by those
skilled in the
art.
In one embodiment all of the dosage forms of the present invention are uniform
in
size prior to coating with the coating layers. The uniform size allows for
uniform coating
thickness and more uniform dissolution of the coating layers.
Enteric polymers are generally applied onto the unit dosage forms as solutions
in
organic or aqueous solvents. The solvents commonly employed as vehicles are
water,
methylene chloride, ethanol, methanol, isopropyl alcohol, acetone, ethyl
acetate and
combinations thereof. The choice of the solvent is based primarily on the
solubility of the
polymer, ease of evaporation, and viscosity of the solution.
Some polymers are also available as aqueous systems. These include Eudragit
L30D
(methacrylic acid-ethyl acrylate ester copolymer marketed by Rohm-Haas GmBH,
West
Germany); Aquateric (cellulose acetate phthalate-containing product marketed
by FMC
Corporation, Philadelphia, Pa.); and Coateric (a polyvinyl acetate phthalate
based product
marketed by Colorcon, Inc., West Point, Pa.). Unlike organic solutions, these
aqueous-based
systems can be prepared at high concentration without encountering high
viscosity. Also,
these aqueous systems do not have the problems associated with the organic
systems such as
flammability, toxicity of the residual solvent in the dosage form, etc.
Coating can be achieved by methods known to one skilled in the art such as by
using
fluidized bed equipment, perforated pans, a regular pharmaceutical pan,
compression coating,
continuous or short spray methods, or by drenching. For example, a plasticized
dispersion of
coating polymer may be applied onto the tablet core comprising the therapeutic
active agent
by spraying using any suitable spray equipment known in the art. In one
embodiment the
solid unit dosage forms are coated by continuous spray methods. In one
embodiment the
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outer coating layer is applied after the inner coating layer but before the
inner coating layer is
dried and/or cured. In yet another embodiment the outer coating layer is
applied
immediately, e.g. within seconds, after the inner coating layer is applied. If
a shiny finish
coat is desired on the solid dosage forms of the present invention, a small
quantity of
polyethylene glycol can be applied to the finished dosage form.
The following non-limiting examples provide typical formulations for
compositions
of the present invention.
Example 1
A wet granulation of 5-ASA (active ingredient), lactose, and povidone is
blended with talc,
magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide.
The blend is
compressed into approximately 1034 mg tablets containing 800 mg of the active
ingredient
on a standard pharmaceutical rotary tablet press.
An inner layer of an EUDRAGIT S coating of 9.2 mg/cm2 dried coating (i.e.
about 62
microns) is applied to the core tablets first by pouring a portion of the
coating formula
without pigments and then by spraying coating onto the tablets. The coating
suspension
sprayed onto the tablets contains approximately 62% by weight on a dry basis
of Eudragit S
and is based in isopropyl alcohol and acetone with dibutylphthalate as the
acting plasticizer.
An outer coating is either applied immediately following the application of
the inner coating
or once the inner coating has cured. The outer coating layer is sprayed onto
the tablets to
achieve of 4.1 mg/cm2 dried coating (i.e. about 28 microns). This coating
suspension
contains approximately 61% by weight on a dry basis of EUDRAGIT S and L in a
ratio of
3:2. It is based in isopropyl alcohol and acetone with dibutylphthalate as the
acting
plasticizer.
Example 2
A wet granulation of 5-ASA (active ingredient), lactose, and povidone is
blended with talc,
magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide.
The blend is
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compressed into approximately 1570 mg tablets containing 1200 mg of the active
ingredient
on a standard pharmaceutical rotary tablet press.
An inner layer of an EUDRAGIT S and L mixture of 8.8 mg/cmZ dried coating
(i.e. about
60 microns) is applied to the core tablets first by pouring a portion of the
coating formula
without pigments and then by spraying coating onto the tablets. The coating
suspension
sprayed onto the tablets contains approximately 61% by weight on a dry basis
of Eudragit S
and L in a ratio of 3:2 and is based in isopropyl alcohol and acetone with
dibutylphthalate as
the acting plasticizer.
An outer coating is applied immediately following the application of the inner
coating or
once the inner coating has cured. The outer coating layer is sprayed onto the
tablets to
achieve of 11.9 mg/cmZ dried coating (i.e. about 80 microns). This coating
suspension
contains approximately 38% by weight on a dry basis of EUDRAGIT L and is
based in
isopropyl alcohol and acetone with triethyl citrate as the acting plasticizer.
Example 3
A wet granulation of 5-ASA (active ingredient), lactose, and povidone is
blended with talc,
magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide.
The blend is
compressed into approximately 690 mg tablets containing 500 mg of the active
ingredient on
a standard pharmaceutical rotary tablet press.
An inner layer of an EUDRAGIT S coating of 15.6 mg/cm2 dried coating (i.e.
about 105
microns) is applied to the core tablets first by pouring a portion of the
coating formula
without pigments and then by spraying coating onto the tablets. The coating
suspension
sprayed onto the tablets contains approximately 62% by weight on a dry basis
of Eudragit S
and is based in isopropyl alcohol and acetone with dibutylphthalate as the
acting plasticizer.
An outer coating is applied immediately following the application of the inner
coating or
once the inner coating has cured. The outer coating layer is a hydroxypropyl
methyllcellulose coating applied to a thickness of about 100 microns of dried
coating
according to the following formula:
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Component Weight per Tablet
Dri-Klear 3.7 g
White Chroma-Tone2 1 g
Water 48 g
1Dri-K1earTM is a mixture of hydroxypropyl methylcellulose, polyethylene
glycol,
hydroxypropyl cellulose, and silicon dioxide, manufactured by CHR Hansen.
2 White Chroma-ToneTM is a mixture of titanium dioxide and hydroxypropyl
methylcellulose
manufactured by CHR Hansen.
Example 4
Core tablets are manufactured to the following formula:
Component Weight per Tablet
Ketoprofen 2 mg
Lactose 4.96 mg
Starch 0.80 mg
Polyvinylpyrrolidone (PVP) 0.16 mg
Magnesium stearate 0.8 mg
CA 02444814 2008-01-14
An inner layer of an EUDRAGITO S coating about 20 microns is applied to the
core tablets
by spraying coating of the following formula:
Component
EUDRAGITO S 100 3 g
Diethyl phthalate 0.75 ml
Silicone fluid 200/20CS 0.75 ml
Methanol 25 parts 100 ml
Dichloromethane 75 parts
An outer coating layer is applied to the core tablet and inner coating layer.
The outer coating
layer is a hydroxypropyl methylcellulose coating applied to a thickness of
about 150 microns
of dried coating according to the following formula:
Component
Dri-Klear 3.7 g
White Chroma-Tone4 1 g
Water 48 g
3Dri-K1ear is a mixture of hydroxypropyl methylcellulose, polyethylene glycol,
hydroxypropyl cellulose, and silicon dioxide, manufactured by CHR Hansen.
'White Chroma-Tone is a mixture of titanium dioxide and hydroxypropyl
methylcellulose,
manufactured by CHR Hansen.
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Example 5
Applied to the core tablets described in Example 4 is an inner layer of an
aqueous
EUDRAGIT L 30 D-55 coating of about 70 microns dried coating of the following
formula:
Component
EUDRAGIT(I L 30 D-55 260 g
Talc 39 g
Polyethylene glycol 6000 16 g
Water 345 g
An outer coating layer is then applied as a hydroxypropyl methylcellulose
coating to a
thickness of about 50 microns of dried coating according to the following
formula:
Component
Dri-Klear 3.7 g
White Chroma-Tone6 1 g
Water 48 g
5Dri-Klear is a mixture of hydroxypropyl methylcellulose, polyethylene glycol,
hydroxypropyl cellulose, and silicon dioxide, manufactured by CHR Hansen.
6White Chroma-Tone is a mixture of titanium dioxide and hydroxypropyl
methylcellulose,
manufactured by CHR Hansen.
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Example 6
The following formulation is encapsulated within soft or hard gelatin
capsules:
Component Weight per Tablet
Insulin 20 i.u. (c.a. 1 mg)
Sodium 5-methoxy salicyclate 150.0 mg
PEG 4000 3.5 mg
PEG 600 187.5 mg
Capsule fill wt 342 mg
Thereafter, the capsule is coated. An inner layer of an EUDRAGITO S coating is
applied to
the capsules by spraying coating of the following formula to a thickness of
about 100 microns
dried coating:
Component
EUDRAGITO S 100 70 g
Triethyl citrate 14 g
Acetone 283 g
Isopropyl Alcohol 483 g
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Following the application of the inner coating, an outer coating layer of an
EUDRAGITO S
and L mixture at a ratio of 2:3 of about 20 microns is applied to the tablets
by spraying a
coating of the following formula:
Component Weight per Tablet
EUDRAGITO L 100 42 g
EUDRAGIT S 100 28 g
Triethyl citrate 14 g
Acetone 283 g
Isopropyl Alcohol 483 g
While particular embodiments of the present invention have been described, it
will be
obvious to those skilled in the art that various changes and modifications of
the present
invention can be made without departing from the spirit and scope of the
invention. It is
intended to cover, in the appended claims, all such modifications that are
within the scope of
this invention.
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