Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL DOSAGE FORM WITH
MULTIPLE ENTERIC POLYMER COATINGS
FOR COLONIC DELIVERY
TECHNICAL FIELD
The present invention relates to novel spherical unit dosage forms to
release therapeutic agents at a point near the inlet to, or within the colon.
BACKGROUND OF THE INVENTION
Release of therapeutically active agents in the colon from a perorally
administered dosage form is desirable in several situations, including: (1)
topical treatment of diseases of the colon such as constipation, irritable
bowel syndrome (IBS), Crohn's disease, ulcerative colitis, carcinomas, and
infection in which systemic absorption of the therapeutic agent is neither
required or desired; (2) systemic absorption of therapeutic agents such as
peptides and proteins which are subject to lumenal degradation in the
stomach and small intestine; and (3) systemic absorption of therapeutic
agents for which peak systemic concentrations and pharmacological activity
are desired at time significantly delayed from the time of peroral administra-
tion (i.e., peak plasma concentrations in the early morning just prior to
arising, from a peroral dosage form ingested at bedtime). Colonic release of
therapeutically active agents from a perorally 'administered dosage form
requires that release of said agent for topical activity or systemic
absorption
be prevented in the stomach and small intestine, but permitted in the colon.
This in turn requires design of the dosage form to be such that it takes
advantage of features of the gastrointestinal tract that indicate arrival of
the
dosage form in the colon, relative to other portions of the gastrointestinal
tract (M. Ashford and J. T. Fell, J. Drug Targeting, 1994, 2:241-258).
Variable features include pH, ionic strength, apparent velocity, and bacterial
content of the lumenal contents of the several anatomical portions of the
gastrointestinal tract as well as the residence time of a pharmaceutical unit
dosage form therein (M. Ashford and J. T. Fell, J. Drug Targeting, 1994,
2:241-258; S. S. Davis, J. Contr. ReL, 1985, 2:27-38).
' The residence time of pharmaceutical unit dosage forms in the
stomach can be particularly variable (M. Ashford and J. T. Fell, J. Drug
Targeting, 1994, 2:241-258): However, the small intestinal transit time of
pharmaceutical unit dosage forms has been demonstrated to be relatively
constant with a mean value of approximately three hours (M. Ashford and J.
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T. Fell, J. Drug Targeting, 1994, 2:241-258). Residence times in the colon
are usually longer than in other portions of the gastrointestinal tract, but
times within the several segments can be highly variable (M. Ashford and J.
T. Fell, J. Drug Targeting, 1994, 2:241-258).
The pH profile of the lumenal contents of the gastrointestinal tract has
also been characterized and found to be relatively consistent (D.F. Evans,
G. Pye, R. Bramley, A. G. Clark, and T. J. Dyson, Gut, 1988, 29:1035-
1041 ). The pH of the stomach may vary temporarily with prandial state, but
is generally below about pH 2. The pH of the small intestine gradually
increases from about 5 to 5.5 in the duodenal bulb to about 7.2 in the distal
portions of the small intestine (ileum). The pH drops significantly at the
ileocecal junction to about 6.3 and very gradually increases to about 7 in the
left or descending colon.
A distinguishing feature of the colon relative to other portions of the
gastrointestinal tract is the presence of exogenous bacteria. These are
capable of enzymatically catalyzing reactions of which the host animal is
incapable.
It has been recognized in general that dosage forms designed for
colonic release may employ one of the following features to indicate arrival
of the dosage form in the colon, relative to other portions of the
gastrointestinal tract: (1) the generally increasing pH profile of the lumenal
contents up to the ileocecal junction; (2) the relatively constant small
intestinal transit time of a pharmaceutical unit dosage form (compensating
for the highly variable stomach residence time); and (3) the presence of
exogenous bacteria in the colon (M. Ashford and J. T. Fell, J. Drug
Targeting, 1994, 2:241-258).
Dosage forms employing the generally increasing pH profile of the
lumenal contents of the gastrointestinal tract as a design feature to indicate
colonic arrival typically employ film coatings of enteric polymers. These
enteric polymers are polyanionic potymers which are insoluble in water and
at low pHs, but begin to dissolve at pHs of about 5. Commercially available
enteric polymers begin to dissolve within the pH range of about 5 to 7.
Examples of the use of this type of rationale to design dosage froms
for delivery to the colon include: USP No. 5,171,580, issued Dec. 7 5, 1992,
Boehringer Ingelheim ttalia, teaches a preparation for delivery in the large
intestine and especially the colon, comprising an active containing core
coated with three protection -layers of coatings having difFerent
solubilities.
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The inner layer is Eudragit~ S, with a coating thickness of about 40-120
microns, the intermediate coating layer is a swellable polymer with a coating
'
thickness of about 40-120 microns, and the outer layer is cellulose acetate
phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate
phthalate, hydroxyethyl cellulose phthalate, cellulose acetate
tetrahydrophthalate, or Eudragit~L. In the dosage forms of the present
invention Eudragit~S is only used as an outer layer.
USP No. 4,910,021, issued on March 20, 1990, Scherer Corp.,
teaches a targeted delivery system wherein the composition comprises a
hard or soft gelatin capsule containing an active ingredient such as insulin
and an absorption promoter. The capsule is coated with a film forming
composition being sufficiently soluble at a pH above 7 as to be capable of
permitting the erosion or dissolution of said capsule. The film forming
composition is preferably a mixture of Eudragit~L, Eudragit~RS, and
Eudragit~S at specific ratios to provide solubility above a pH of 7.
USP No. 4,432,966, issued on Feb. 21, 1984, Roussel-UCLAF,
teaches a compressed tablet with an active agent, coated with a first coating
layer comprising a mixture of microcrystalline cellulose and lower alkyl ether
of a cellulose film-forming organic polymer such as ethyl cellulose, and a
second coating layer selected from cellulose acetylphthalate, hydroxypropyl
methylcellulose phthalate, benzophenyl salicylate, cellulose acetosuccinate,
copolymers of styrene and of malefic acid, formulated gelatin, salol, keratin,
steraric acid, myristic acid, gluten, acrylic and methacrylic resins, and
copolymers of malefic acid and phthalic acid derivatives.
Using pH as an indicator of colonic arrival of the dosage form
presents some difficulties. Although the pH of the lumenal contents
gradually increases from the stomach through the small intestine, the pH of
the lumenal contents of the proximal portions of the colon is lower than that
of the distal small intestine (ileum). This is due to the presence of short
chain fatty acids produced by the action of exogenous bacteria in the colon.
Therefore, a given pH value does not distinguish the colon from various
portions of the small intestine. A dosage form designed to release the
' therapeutic agent at the pH of the proximal colon would also release the
therapeutic agent at those portions of the small intestine proximal to the
' ileum within which the pH is similar to that of the proximal colon. Thus,
the
validity of the use of enteric coatings to attain colonic release has been
questioned (M. Ashford and J. T. Fell, J. Drug Targeting, 1994, 2:241-258;
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M. Ashford, J. T. Fell, D. Attwood, and P. J. Woodhead, Int. J. Pharm.,
1993, 91:241-245; M.Ashford, J. T. Fell, D. Attwood, H. L. Sharma, and P. J.
Woodhead, Int. J. Pharm., 1993, 95:193-199)
Although lumenal content pH alone does not distinguish the colon
from various other portions of the small intestine, pH does distinguish the
stomach from the small intestine and colon. Enteric polymer coatings have
been extensively used in the prior art to distinguish the stomach from the
small intestine and prevent release of a therapeutic agent until the dosage
form has emptied from the stomach. This use has resulted in an extensive
history confirming the safety of these polymers, a large literature describing
suitable processes for application of these polymers as coatings to dosage
forms, and the commercial availability of a number of suitable enteric
polymers.
It has been recognized that dosage forms that delay release of a
therapeutic agent for a time period corresponding to the stomach and small
intestine residence times will provide colonic delivery (S. S. Davis, J.
Contr.
Rel., 1985, 2:27-38). This has been primarily based upon the reasonably
constant residence time in the small intestine, assuming that the additional
use of an enteric polymeric coating will compensate for variable stomach
residence times by preventing activation of the time based delay mechanism
until the dosage form has reached the small intestine. Proposed time delay
mechanisms have been based upon slow dissolution of pH independent _
coatings (A. Gazzaniga, P. lamartino, G. Maffione, and M. E. Sangalli,
Proceed. 6th Int. Conf. on Pharm. Techn. (Paris) 305-313, 1992), controlled
pH independent, permeation of water through a coating to activate
disintegration of the dosage form by osmotic pressure (F. Theeuwes, P. L.
Wong, T. L. Burkoth, and D. A. Fox, in Colonic Drug Absorption and
Metabolism, P. R. Bieck, ed., Marcel Dekker, Inc., New York, Basel, Hong
Kong, 137-158 (1993)) or by physical swelling (R. Ishino, H. Yoshino, Y.
Kirakawa, and K. Noda, Chem. Pharm. Bull., 1992, 40:3036-3041), or
swelling and ejection of a plug by pH independent hydration (I. R. Welding,
S. S. Davis, M. Bakhshaee, H. N. E. Stevens, R. A. Sparrow, and J.
Brennan, Pharm. Res., 1992, 9:654-657). Such approaches have not been
completely satisfactory for reasons of size, reproducibility of time to
release,
complexity, and expense.
Although enteric polymers have a long history of commercial use and
inherently compensate for variable stomach residence times, their use to
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provide a time based delay in therapeutic agent release based upon
dissolution of an enteric polymer coating has not been advocated. This is
presumably due to the variability in enteric polymer dissolution as a function
of the varying pH and velocity of the lumenal contents of the small intestine
and colon. However, a dosage form employing an enteric polymer to
achieve colonic release based upon dissolution time of the enteric polymer
coating has advantages in terms of proven safety of these polymers and
commercially feasible application processes.
It is an object of the present invention to provide colonic release of
therapeutic agents from a unit dosage form by employing distinct, multiple
coatings or layers of enteric polymers as the means of delaying release of
the therapeutic agent until the dosage form has reached the proximal colon.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition in a
unit dosage form for peroral administration in a human or lower animal,
having a gastrointestinal tract comprising a small intestine and a colon with
a lumen therethrough having an inlet to the colon from the small intestine,
comprising:
a. a safe and effective amount of a therapeutically active agent
incorporated into or coated on the surface of a dosage form
selected from the group consisting of a spherical substrate, an
elliptical substrate, a hard capsule, or a compressed tablet,
with a maximum diameter of about 3 mm to about 10 mm; and
b. an enteric polymer coating material comprising at least one
inner coating layer and one outer coating layer;
wherein the dosage form has a smooth surface free from edges or sharp
curves; the elliptical substrate and the hard capsule have a ratio of the long
to short diameters of no greater than about 1.5; the therapeutically active
agent is released at a point near the inlet to, or within the colon; each of
the
inner coating layers) 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 between about 6.8 to about 7.2.
DETAILED DESCRIPTION OF THE INVENTION
The use of enteric polymers to delay release of a therapeutic agent
from a pharmaceutical unit dosage form until said dosage form has reached
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the colon has not been entirely successful. Reasons for the lack of success
include:
a. the decrease in the pH of the lumenal contents of the proximal
colon relative to the terminal small intestine (ileum) which oviates the use
of
pH as a recognition factor for colonic delivery as described previously;
b. the difficulty of designing an enteric polymer coating over a unit
dosage form that will completely dissolve during the residence time of the
dosage form in the small intestine due to the varition in pH and velocity of
the lumenal contents of the small intestine and colon; and
c. thin spots in the enteric polymer coating that develop over edges
and sharp curves in conventional unit dosage forms resulting in premature
rupture of the enteric polymer coating and release of the therapeutic agent.
The enteric polymer coated dosage forms of the present invention
are designed to delay release of the therapeutic agent for a period of time
approximately corresponding to the residence time in the small intestine,
rather than employing a given pH value as a recognition factor for colonic
arrival. This eliminates the problem introduced by the decrease in pH in the
proximal colon relative to the ileum.
The inventors have discovered that the amounts and types of enteric
polymers required to delay release of the therapeutic agent for a time
approximately corresponding to the residence time in the small intestine can
be determined by 1. a knowledge of the dissolution behavior of the selected
enteric polymer as a function of the size of the dosage form and the pH and
velocity of an aqueous medium, and 2. by an estimation of the pH and
apparent velocity of the lumenal contents of the sequential anatomical
segments of the small intestine and colon. Since final dissolution of the
enteric coating is desired to occur in the colon, the enteric polymer or
polymers comprising the coating of the unit dosage form must be selected
and applied to the dosage form such that the coating will be soluble when
the dosage form is in the proximal portion of the colon, or at a maximum pH
of about 6.3. If a single enteric polymer coating is used, the amounts of
enteric polymer required to achieve the requisite delay in release of the
therapeutic agent are relatively large and greatly in excess of those revealed
in the prior art (See WO 96/36319. However, the total amount of enteric
polymer coating required to achieve colonic release can be reduced if
distinct, multiple enteric polymer coating layers are used. The outermost
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layer consists of an enteric polymer that begins to dissolve at about pH 6.8
to 7.2 in an amount such that this coating layer is completely dissolved
within the distal portion of the small intestine (ileum). The inner coating
layer or layers consist of enteric polymers that begin to dissolve at about pH
5.0 to 6.3 in an amount such complete dissolution substantially occurs within
the proximal colon. Thus, the function of the outermost coating layer is to
prevent release of the therapeutic agent as the dosage form transits the
gastrointestinal tract to the distal small intestine, and the function of the
inner coating layers is to further delay release of the therapeutic agent
until
the dosage form has reached the proximal colon.
It is desirable in dosage forms of the present invention that the
enteric polymer coatings essentially completely dissolve prior to release of -
the therapeutic agent in order to assure that the predicted dissolution time
for given amounts of enteric polymer coatings corresponds to the time
release of the therapeutic agent is delayed. This requires uniform enteric
polymer film coating thicknesses over the dosage forms. Thin spots in the
enteric polymer coatings can occur over edges and sharp curves of
conventional dosage forms and can result in premature rupture of the
enteric polymer coating and release of the therapeutic agent. Therefore,
dosage forms of the present invention are spherical or eliptical in shape, of
a
nearly uniform particle size, with smooth surfaces essentially free from
edges or sharp curves in order to facilitate the application of a enteric
polymer coating of uniform thickness over each of the unit dosage forms.
The present invention relates to a pharmaceutical composition in a
unit dosage form for peroral administration in a human or lower animal,
having a gastrointestinal tract comprising a small intestine and a colon with
a lumen therethrough having an inlet to the colon from the small intestine,
comprising:
a. a safe and effective amount of therapeutically active agent
incorporated into or coated on the surface of a dosage form
selected from the group consisting of a spherical substrate, an
elliptical substrate, a hard capsule, or a compressed tablet,
with a maximum diameter of about 3 mm to about 10 mm; and
b. an enteric polymer coating material comprising at least one
' inner coating layer and one outer coating layer;
wherein the dosage form has a smooth surface free from edges or sharp
curves; the elliptical substrate and the hard capsule have a ratio of the long
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to short diameters of no greater than about 1.5; the therapeutically active
agent is released at a point near the inlet to, or within the colon; each of
the
inner coating layers) is an enteric polymer that begins to dissolve in an
aqueous media at a pH between about 5 to about fi.3; and the outer coating
layer is an enteric polymer that begins to dissolve in an aqueous media at a
pH between about 6.8 to about 7.2.
The dosage forms of the present invention are to be distinguished
from controlled (sustained) release compositions which slowly release a
therapeutic agent over an extended period of time and extend the duration
of therapeutic action over that achieved with conventional delivery. The
dosage forms of the present invention prevent the release of the drug active
until the dosage form reaches the colon. The subsequent rate of release of
the therapeutic agent will vary from rapid to slow depending upon the
pharmacodynamic requirements of the specific therapeutic agent.
Preferably, the enteric polymer coating material has one inner coating
layer and one outer coating layer.
Therapeutically active agient
The methods and compositions of the present invention comprise a
safe and effective amount of therapeutically active agent. The phrase "safe
and effective amount", as used herein, means an amount of therapeutically
active agent 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 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 Pike
factors.
Therapeutic agents suitable for incorporation into dosage forms of
the present invention are those for which release in the colon or delayed
release is therapeutically advantageous. These include therapeutic agents
useful for topical treatment of diseases of the colon such as constipation,
diarrhea, irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis,
carcinomas, and infection in which systemic absorption of the therapeutic
agent is neither required or desired. These include laxatives such as
picosulfate and sennasides, anti-diarrheals such as loperamide,
nonsteroidal anti-inflammatory drugs such as 5-amino salicylic acid,
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glucocorticoids such as dextramethazone, antimicrobials, especially those .
effective against anaerobic microbes such as methotrexate,
immunosupressants such as cyclosporine A, and chemotherapeutics for
treatment of carcinomas.
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, el., 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 than enhances the absorption of the macromolecule (M. Mackay
and E. Tomlinson, in Colonic Drug Absorption and Metabolism, P. R. Bieck,
el., Marcei Dekker, Inc., New York, Basel, Hong Kong, 137-158 (1993)).
Colonic release is also desirable for systemic absorption of
therapeutic agents for which peak systemic concentrations and
pharmacological activity are desired at time significantly delayed from the
time of peroral administration (i.e., peak plasma concentrations in the early
morning just prior to arising from a peroral ' dosage form ingested at
bedtime). This is particularly advantageous for conditions such as asthma,
arthritis, inflammation, coronary infarction, and angina pectoris which are
susceptible to diurnal rhythms (B. Lemmer, in Pulsatile Drug Delivery, R.
Gurny, H. E. Junginger, and N. A. Pepas, eds, Wissenschaftliche
Verlagsgesellschaft mbH, Stuttgart, 11-24 (1993)). Drugs for which laity
variations in their effects have been reported in clinical studies include
cardiovascularly active drugs such as beta-blockers (acebutolol,
propranolol), calcium channel blockers {verapramil), and ACE inhibitors
(enalapril), anticancer drugs such as cisplatin and duxorubicin, antiasthmatic
drugs such as theophylline, psychotropic drugs such as diazepam, H1-
Antihistamines such as terfenadine, nonsteroidal anti-inflammatory drugs
such as flurbiprofen, naproxen, and piroxicam, and H2-blockers such as
cimetidine and ranitidine.
The therapeutically active agent may be incorporated onto the
surface of or into one of the several substrates described herein in a manner
consistent with the physical chemical properties of the drug and its
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pharmacodynamics using techniques known to those skilled in the art. It is
recognized that the rate of release of the therapeutically active agent in the
colon will be dependent upon the manner of incorporation of the
therapeutically active agent and the nature and levels of any excipients.
The rate of release should be such that the therapeutic activity of the agent
is maximized.
As used herein, "excipient" means any component admixed with or
co-incorporated with the therapeutically active agent onto the surface of or
into the substrate. Excipients may act to facilitate incorporation of the
therapeutically active agent onto or into the substrate, modify the release of
the therapeutically active agent from the substrate, 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 and compatible with the therapeutically active
agent. 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 facilitation of dosage
form
manufacture.
The Dosage Form
A safe and effective amount of therapeutically active agent is
incorporated into or coated on the surtace of a dosage form selected from
the group consisting of a spherical substrate, an elliptical substrate, a hard
capsule, or a compressed tabtet, with a maximum diameter of about 3 mm
to about 10 mm; wherein the dosage form has a smooth surface free from
edges or sharp curves; the elliptical substrate and the hard capsule have a
ratio of the long to short diameters of no greater than about 1.5.
Preferably the dosage forms of the present invention are selected
from the group consisting of a soft gelatin capsule; molded sphere or
ellipsoid made from any pharmaceutically acceptable excipient that can be
melted or molded; a sphere prepared by coating a substrate onto a seed
crystal made of any irnert pharmaceutically acceptable excipient; hard
capsules without edges, having flat seals; and compressed tablets, wherein
the dosage form has a smooth surface free from edges or sharp curves, and
the elliptical substrate and the hard capsule have a ratio of the long to
short
diameters of no greater than about 1.5.
As used herein, "elliptical substrate" means an ellipsoid, a solid figure
in which all plane surfaces are elipses or circles, described by the equation
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x2/a2 + y2/b2 + z2/c2, wherein b = c, a/b _< 1.5, and "a" is between 3 and 10
mm.
As used herein, "smooth surface free from edges or sharp curves"
means that no edges exist on the dosage form sufficient to produce thin
spots in the enteric coating relative to the mean coating thickness.
Especially preferred dosage forms are spheres with a diameter of about 3
mm to about 8 mm; more preferably about 4 mm to about 7 mm. Preferably
all of the dosage forms are of a uniform size prior to coating with the
polymer coating material. Preferably, the diameters of substantially all of
the spheres are within about 5%, more preferably about 2%, of the mean
diameter. The smooth surface and uniform size allow for uniform coating
thickness and uniform dissolution of the polymer coating material.
The dosage form preferably consists of an inert spherical substrate
prepared by coating and/or layering processes such as sugar spheres, NF.
These substrates are sized prior to coating to obtain the desired uniform
diameter by sieving and/or weighing, i.e., separated by using a weight
checker. Preferably the diameters of substantially all of the spheres are
within about 5%, more preferably about 2%, of the mean diameter. They
are subsequently coated with the therapeutically active agent. The
therapeutically active agent is preferrably bound to the sugar sphere
substrate with a water soluble, inert polymer, preferably low viscosity
hydroxypropyl cellulose or hydroxypropyl methylcellulose. The ratio of the
binding polymer to the therapeutically active agent is from about 1:10 to
10:1; preferably from about 1:5 to 5:1; more preferably from about 1:4 to 1:1.
The coating of the therapeutically active agent on the sugar sphere
may be optionally overcoated with an inert, water soluble polymer, to a
thickness of about 10 pm to about 50 Vim; preferably about 20 p,m to about
40 pm. This overcoat is referred to herein as a barrier coating. The barrier
coating preferably consists of low viscosity hydroxypropyl methylcellulose.
When the substrate is a sugar sphere and when the innermost enteric
polymer coating material is cellulose acetate phthalate, then preferably the
dosage form also comprises a barrier coating between the therapeutically
active agent and the cellulose acetate phthalate. The coating of active
agent and the barrier coating may be applied to the commercially available
inert spherical substrate by any number of processes well known to those
skilled in the art, including, but not limited to, perforated pan coating and
fluid bed coating.
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The dosage form may also perferably comprise an inert molded
spherical or elliptical substrate. As used herein, "molding" refers to a
process in which a molten or semi-solid inert, pharmaceutically acceptable
material is injected into a mold cavity and allowed to solidify. The
dimensions of the mold cavity thereby determine those of the substrate.
Suitable materials include, but are not limited to, ingestible
pharmaceutically
acceptable waxes such as beeswax, paraffins, carnuba wax, and
triglycerides with a melting point above about 50°C such as tristearin,
and
higher molecular weight polyethylene glycols with a melting point above
about 50°C. The therapeutically active agent may be incorporated into
the
substrate during the molding process or coated onto molded substrates and
optionally overcoated with a water soluble, inert polymer as described
above. '
A further preferred 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.
A still further preferred unit dosage form is a hard capsule (i.e. starch
or gelatin hard capsules) without edges, having flat seals where the long to
short diameter is no greater than 1.5. An example is a starch capsule free
from surfaces edges available under the trade mark 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 starch 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.
An additional preferred unit dosage form is a compressed spherical
or elliptical tablet with a maximum diameter of about 3 to about 10 mm free
from surface edges and sharp curves. The tablet is comprised of a solid
form of therapeutically active agent and is compressed using conventional
equipment and processes.
The Enteric Polymer Coating Material
In the compositions of the present invention, the polymer coating
material prevents the release of therapeutically active agent as the dosage
form passes through the upper gastrointestinal tract, including the mouth,
esophagus, stomach, and small intestine, until the dosage form is near the
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junction between the small intestine and the colon or is in the colon. This
precludes systemic absorption of therapeutically active agent from the upper
gastrointestinal tract and/or dilution of the released therapeutically active
agent in the contents of the upper gastrointestinal tract. Therefore, the
polymer coating materials, in combination with a spherical or elliptical
substrate with a smooth surface provides a method of delivering the
therapeutically active agent in a concentrated form to the colon.
As used herein, "enteric polymer coating material", refers to materials
which completely surround and encase the therapeutically active agent in
the unit dosage form prior to oral administration. The polymer coating
material of the present invention does not contain any active compound, i.e.
therapeutically active agent, of the present invention. In addition the
present invention does not comprise enteric coated microcrystal spheres or
particles of the active compound or enteric coated granules of the active
compound. Preferably, a substantial amount or all of the enteric polymer
coating material is dissolved before the therapeutically active agent is
released from the dosage form, so as to achieve delayed dissolution of the
therapeutically active agent.
The polymer coating materials are selected such that therapeutically
active agent will be released at about the time that the dosage form reaches
the inlet between the small intestine and the colon, or thereafter in the
colon.
The selection is based upon the pH profile of the small intestine and colon.
The pH of the small intestine gradually increases from about 5 to 5.5 in the
duodenal bulb to about 7.2 in the distal portions of the small intestine
(ileum). The pH drops significantly at the ileocecal junction to about 6.3 and
very gradually increases to about 7 in the left or descending colon. In order
to provide a predictable dissolution time corresponding to the small
intestinal
transit time of about 3 hours and permit reproducible release of drug at the
inlet between the small intestine and the colon, or thereafter in the colon,
the
coating should begin to dissolve within the pH range of the small intestine
and continue to dissolve at the pH of the proximal colon. This means that a
single coating layer of a single enteric polymer coating material should begin
to dissolve in the pH range of about 5 to 6.3, which requires a minimum
coating thickness of 250 Nm. (See WO 96/36319). Single layer coatings of
enteric polymer coating materials which begin to dissolve at higher pH
levels, such as about 7, require less coating thickness for the
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14
dosage form to reach the inlet between the small intestine and the colon, or
the colon. However, any coating remaining when the dosage form reaches
the colon will not dissolve in the proximal portions of the colon where the pH
is less than 7, thus delaying drug release until the dosage form has reached
a portion of the colon where the lumenal pH is greater than 7.
In order to provide for release in the proximal colon while minimizing
total enteric polymer coating thickness, the enteric polymer coating materials
of the present invention consist of a sequential coating of multiple,
preferably two, materials in distinct, multiple layers. The outer coating
layer
consists of an enteric polymer coating material which begins to dissolve at a
pH between about 6.8 to about 7.2 in an amount such that this layer is
completely dissolved when the dosage form is in the distal small intestine:-
The inner layer, or layers, consists) of enteric polymer coating materials)
that begin to dissolve at pHs between about 5 to about fi.3, preferably a pH
between about 5 to about 6, more preferably a pH between about 5 to about
5.5. The amounts) of the inner layers) is(are) such that release of the drug
is delayed until the dosage form has reached the inlet between the small
intestine and the colon, or the colon. Thus, the function of the outer coating
layer of enteric polymer coating material is to prevent release of the drug
from the stomach through to the distal portion of the small intestine, and the
function of the inner coating layers) is to prevent release of the drug from
the distal portion of the small intestine (from the time the outermost layer
has dissolved) to the inlet between the small intestine and the colon, or the
colon.
Preferred coating materials for the outer coating layer of enteric
polymer coating material include pH-sensitive materials, which remain intact
in the lower pH environs of the stomach and smallintestine, but begin to
dissolve in an aqueous solution at a pH between about 6.8 to about 7.2.
The coating thickness is dependent upon the size of the unit dosage form,
but ranges from about 20 ~m to about 50 p.m. Preferred materials for the
outer coating layer of enteric polymer coating material are poly(methacrylic
acid, methyl methacrylate) 1:2 (Eudragit~ S), and mixtures of
poly(methacryiic 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 1:2, preferably about 1:5 to about 1:3. Especially
preferred is Eudragit~ S.
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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; Eudragit~ S is an anionic copolymer derived
from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl
groups to the ester groups of approximately 1:2, and a mean molecular
weight of approximately 135,000, from Rohm Tech.
Preferred coating materials for the inner coating layers) include pH-
sensitive materials, which remain intact in the lower pH environs of the
stomach and small intestine, but which disintegrate or dissolve at the pHs
commonly found in the distal portion of the small intestine and especially, in
the proximal colon. The inner coating layer polymers have a low apparent
pKa range to minimize the impact of the drop in the pH across the ileo-cecal
valve. The inner coating layer enteric polymers) begins to dissolve in an
aqueous solution at a pH between about 5 to about 6.3. It is particularly
important that the enteric polymers) be soluble in the proximal portion of the
colon where the lumenal pH is typically lower than that in the distal portions
of the small intestine due to the presence of short chain fatty acids produced
by the metabolic activity of bacteria residing in the colon.
The enteric polymer coating materials for the inner layers) are
selected from the group consisting of cellulose acetate phthalate; cellulose
acetate trimelliate; hydroxypropyl methylcellulose phthalate; hydroxypropyl
methylcellulose acetate succinate; polyvinyl acetate phthalate;
poly(methacrylic acid, methyl methacrylate) 1:1; poly(methacrylic acid, ethyl
acrylate) 1:1; and compatable mixtures thereof, preferably poly(methacrylic
acid, methyl methacrylate) 1:1 and poly(methacrylic acid, ethyl acrylate)
1:1, and compatable mixtures thereof, more preferably poly(methacryiic
acid, ethyl acrylate) 1:1.
Specific examples of these polymer coating materials include the
following: Eudragit~ L, 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;
Eudragit~ L 30 D, 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
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16
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, 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.
A preferred polymer coating material is poly(methacrylic acid, ethyl
acrylate) 1:1 (Eudragit~ L 100-55), wherein for diameters of about 4 to
about 7 mm, the preferred coating thickness is about 120 to 350 ~m and
about 100 to 300 Vim, respectively.
Another preferred polymer is poly(methacrylic acrd, methyl
methacrylate) 1:1 (Eudragit~ L), wherein for diameters of about 4 to about 7
mm, the preferred coating thicknesses is about 110 to 300 pm and about 90
to 250 Vim, respectively.
The total amount of enteric polymer coatings on the dosage form
must be sufficient such that complete dissolution of the coating does not
occur until the dosage form is at a location within the gastrointestinal tract
near the opening to, or within the colon, thereby releasing therapeutically
active agent in the colon. This necessitates the requirement of a spherical
or elliptical dosage form free from surface edges or sharp curves which will
produce thin spots in the coatings. The coatings over such thin spots will
dissolve prior to the dosage form reaching the colon, resulting in premature
release of therapeutically active agent.
Transit of pharmaceutical dosage forms through the gastrointestinal
tract has been characterized in the literature (i.e., M. Ashford and J. T.
Fell,
J. Druc~Tarqetinq, 1994, 2:241-258). Gastric emptying of pharmaceutical
dosage forms can be highly variable, but transit through the small intestine
is relatively constant with a mean transit time of about three hours. The pH -
solubility behaviors of the enteric polymers of the present invention are such
that significant dissolution of the enteric polymer coating will not occur
until
CA 02271569 2002-O1-15
17
the dosage form has emptied from the stomach, thereby eliminating the
varibility of gastric emptying as a factor in determining the amount of
coating
required to achieve release of therapeutically active agent in the colon.
Therefore, the amount of enteric polymer coatings should be such that it is
substantially dissolved during the approximate three hour transit time of the
small intestine.
Dissolution of the enteric polymers of the present invention is
influenced by the size of the dosage form, and the pH, ionic strength, and
velocity of the surrounding aqueous medium. The latter three factors vary
throughout the length of the small intestine and colon. In addition, the
effect
of these factors upon dissolution rate varies with each enteric polymer.
However, the amount of a single coating layer of enteric polymer is
substantial, wherein the enteric polymer is soluble in the proximal portions
of
the colon, as taught in WO 96/36319. An important
aspect of the present invention is the use of multiple
coating layers of enteric polymers in which the outermost
layer consists of an enteric polymer or combination of
enteric polymers which are insoluble below about pH 6.8. The inner layers)
consist of enteric polymers) that begin to dissolve at a pH between about 5
to about 6.3 in order to be soluble in the proximal portions of the colon. The
use of multiple layers in the manner described herein reduces the total
amount of enteric polymer coating relative to the use of a single coating
layer of enteric polymer that is soluble in the proximal portions of the
colon.
The more important parameters for determination of the amount of
enteric polymer required to delay drug release until the dosage form has
reached the colon have been found to include the pH solubility profiles of
the enteric polymers employed in the outermost and inner coating layers
and the size of the dosage form. Approximate minimum amounts of enteric
polymer as a function of the pH at which the polymer begins to dissolve and
dosage form size are shown in the following table, Table 1. Also included
are examples of enteric polymers.
Table 1
Minimum Example Enteric Polymers
DiameterLayer pH Thickness
(mm) (gym)
3 Inner 5.0 150 HPMCP 50
3 Outer 7.0 40 Eudragit~ S
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18
Inner 5.0 130 HPMCP 50
5 Outer 7.0 30 Eudragit~ S
Inner 5.0 100 HPMCP 50
10 Outer 7.0 20 Eudragit~ S
3 Inner 5.5 140 Eudragit~ L100-55
3 Outer 7.0 40 Eudragit~ S
5 Inner 5.5 120 Eudragit~ L100-55
5 Outer 7.0 30 Eudragit~ S
10 Inner 5.5 90 Eudragit~ L100-55
10 Outer 7.0 20 Eudragit~ S
3 Inner 6.0 130 Eudragit~ L
3 Outer 7.0 40 Eudragit~ S
5 Inner 6.0 110 Eudragit~ L
5 Outer 7.0 30 Eudragit~ S
10 Inner 6.0 80 Eudragit~ L
10 Outer 7.0 20 Eudragit~ S
The enteric polymer coating material may by applied to the spherical
or elliptical substrate as a solution in a pharmaceutically acceptable solvent
such as ethanol, acetone, isopropanol, ethyl acetate, or mixtures thereof; as
an aqueous solution buffered with amminium hydroxide; or as a fine
dispersion in water using any number of processes known to one skilled in
the art, including but not limited to, perforated pan coating and fluid bed
coating.
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,
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; preferably the plasitcizer is dibutyl phthalate 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
piasticizer, preferably from about 0% to about 25% by weight, more
preferably from about 10% to about 20% by weight of the enteric polymer.
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19
fn addition, to facilitate the coating process, the coating material may
also comprise inert solid particulates. Preferred inert solid particulates
include talc and titanium dioxide.
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 used and the type of dosage form used according to criteria
known to those skilled in the art.
Method of Making
Enteric polymers are generally applied onto the spherical or elliptical
substrates as solutions in organic solvents. The solvents commonly
employed as vehicles are 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. Currently,
three aqueous enteric polymer coatings are available for commercial use in
the United States. These are 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, etc. by continuous or short spray
methods, or by drenching.
The following non-limiting examples provide typical formulations for
compositions of the present invention.
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Example 1
dosage form of the following formulation is prepared as described
below:
Substrate Barrier Coat
Component Wt. (mg) Component Wt
(mg)
Sugar Sphere, USP 212 HPMC, USP1 5
Dextramethasone 3
HPMC, USP1 1
Inner Enteric Coat Outermost Enteric
Coat
Component Wt. (mg) Component Wt.
(mg)
Eudragit~ L100- 18 Eudragit~ S3 5
552
Dibutyl Phthalate4 Dibutyl Phthalate1
Talc, USP 8 Red Ferric Oxide1
Talc, USP 2
~ Hydroxypropyl Methylcellulose, USP. Methocel~ E15LV, Dow Chemical.
2Poly(methacrylic acid, ethyl acrylate) 1:1, Eudragit~ L100-55, Rohm Tech.
3Poly(methacrylic acid, methyl methacrylate) 1:2, Eudragit~ S, Rohm Tech.
Substrate
Dextramethasone is dispersed in water at a level of 2.7% by weight
with 0.9% by weight HPMC as a binding polymer and sprayed onto sugar
spheres (6.53 - 6.63 mm diameter) in a perforated pan coater maintaining
an outlet aiNbed temperature of about 40°C.
Barrier Coat
HMPC is dissolved in water to produce a 4% by weight solution which
is coated on the substrates described above in a perforated pan coater
maintaining an outlet air/bed temperature of about 40°C.
Inner Enteric Coat
Eudragit~ L100-55 and dibutyi phthalate are dissolved in a solution of
isopropanol, acetone, and water (37:9:1) at levels of 8.0% and 1.6% (total
weight percent), respectively. Talc is then suspended in the solution at a
levels of 3.3% by weight. The resulting mixture is coated onto the barrier
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21
coated substrates above in a perforated pan coater maintaining an outlet
air/bed temperature of about 30°C.
Outermost Enteric Coat
Eudragit~ S and dibutyl phthalate are dissolved in a solution of
isopropanol, acetone, and water (37:9:1 ) at levels of 8.0% and 1.6% (total
weight percent), respectively. Red ferric oxide and talc are then suspended
in the solution at levels of 1.2% and 2.1 % by weight, respectively. The
resulting mixture is coated onto the barrier coated substrates above in a
perforated pan coater maintaining an outlet aiNbed temperature of about
30°
C.
Example 2
A dosage form of the following formulation is prepared as described
below:
S a bstrate
Component ~. (mg)
Medium Chain Triglyceridel 63
Polyoxyl 35 Castor Oil, NF
Poloxamer 182 20
Propanolol Base 15
#3 Spherical Soft Elastic GelatinN/A
Capsule
Inner Enteric Outermost Enteric
Coat Coat
Component Wt. (mg) Component Wt. (mg)
Eudragit~ L100- 18 Eudragit~ S3 5
552
Dibutyl Phthalate4 Dibutyl Phthalate1
Talc, USP 8 Red Ferric Oxide1
Talc, USP 2
A ... if1 _
'v.apiex~ 3UU, Hti) 1 tC: (;Orp.
2Poly(methacrylic acid, ethyl acrylate) 1:1, Eudragit~ L100-55, Rohm Tech.
3Poly(methacrylic acid, methyl methacrylate) 1:2, Eudragit~ S, Rohm Tech.
Substrate
Medium chain triglyceride, polyoxyl 35 castor oil, and poloxamer 182
are blended to produce a solution of a self emulsifying lipid. Propanolol
base is subsequently dissolved in the self emulsifying lipid vehicle which is
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22
then filled into a #3 soft elastic gelatin capsule at a level of 100 mg using
conventional equipment.
Inner Enteric Coat
Eudragit~ L100-55 and dibutyl phthalate are dissolved in a solution of
isopropanol, acetone, and water (37:9:1 ) at levels of 8.0% and 1.6% (total
weight percent), respectively. Talc is then suspended in the solution at a
levels of 3.3% by weight. The resulting mixture is coated onto the barrier
coated substrates above in a perforated pan coater maintaining an outlet
air/bed temperature of about 30°C.
Outermost Enteric Coat
Eudragit~ S and dibutyl phthalate are dissolved in a solution of
isopropanol, acetone, and water (37:9:1 ) at levels of 8.0% and 1.6% (total
weight percent), respectively. Red ferric oxide and talc are then suspended
in the solution at levels of 1.2% and 2.1 % by weight, respectively. The
resulting mixture is coated onto the barrier coated substrates above in a
perforated pan coater maintaining an outlet air/bed temperature of about
30°
C.
Example 3
A dosage form of the following formulation is prepared as described
below:
Substrate
- Component VIII. (mg)
Sugar Sphere, USP 50
Mesalamine 200
HPMC, USP1 50
Inner Enteric Outermost Enteric
Coat Coat
Component Wt. (mg) Component Wt.
(mg)
Eudragit~ L2 8 Eudragit~ S3 3
Dibutyl Phthalate1.6 Dibutyl Phthalate0.6
Talc, USP 3 Red Ferric Oxide0.5
Talc, USP 1
~ Hydroxypropyl Methylcellulose, USP. Methocei~ E15LV, Dow Chemical.
2Poly(methacrylic acid, methyl methacrylate) 1:1, Eudragit~ L, Rohm Tech.
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23
3Poly(methacrylic acid, methyl methacrylate} 1:2, Eudragit~ S, Rohm Tech.
Substrate
Mesalamine is coated onto sugar spheres (2.9 - 3.1 mm diameter)
. - using a binding solution of 10% by weight HPMC in water in a CF
Granuiator (Vector Corp.).
Inner Enteric Coat
Eudragit~ L and dibutyl phthalate are dissolved in a solution of
isopropanol, acetone, and water (37:9:1 ) at levels of 8.0% and 1.6% (total
weight percent), respectively. Talc is then suspended in the solution at a
levels of 3.3% by weight. The resulting mixture is coated onto the barrier
coated substrates above in a perforated pan coater maintaining an outlet
air/bed temperature of about 30°C.
Outermost Enteric Coat
Eudragit~ S and dibutyl phthalate are dissolved in a solution of
isopropanol, acetone, and water (37:9:1 ) at levels of 8.0% and 1.6% (total
weight percent), respectively. Red ferric oxide and talc are then suspended
in the solution at levels of 1.2% and 2.1 % by weight, respectively. The
resulting mixture is coated onto the barrier coated substrates above in a
perforated pan coater maintaining an outlet aiNbed temperature of about
30°
C.
Example 4
A dosage form of the following formulation is prepared as described
below:
~..~~,~.
Substrate
Component ~, (mg)
Oleic Acid 30
Polyoxyl 60 Hydrogenated 69.5
Castor Oil, NF
Salmon Calcitonin 0.5
#3 Spherical Soft Elastic NIA
Gelatin Capsule
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24
Inner Enteric Outermost Enteric
Coat Coat
Component Wt. (mg) Component Wt.
(mg)
Eudragit~ L100- 18 Eudragit~ S2 5
551
Dibutyl Phthalate4 Dibutyl Phthalate1
Talc, USP 8 Red Ferric Oxide1
Talc, USP 2
1 Poly(methacrylic acid, ethyl acrylate) 1:1, Eudragit~ L100-55, Rohm Tech.
2Poly(methacrylic acid, methyl methacrylate) 1:2, Eudragit~ S, Rohm Tech.
Substrate
Oleic acid and polyoxyl 60 hydrogenated castor oil are blended to
produce a solution. Salmon calcitonin is subsequently dispersed in the self
emulsifying lipid vehicle which is then filled into a #3 soft elastic gelatin
capsule at a level of 100 mg using conventional equipment.
Inner Enteric Coat
Eudragit~ L100-55 and dibutyl phthalate are dissolved in a solution of
isopropanol, acetone, and water (37:9:1 ) at levels of 8.0% and 1.6% (total
weight percent), respectively. Talc is then suspended in the solution at a
levels of 3.3% by weight. The resulting mixture is coated onto the barrier
coated substrates above in a perforated pan coater maintaining an outlet
airlbed temperature of about 30°C.
Outermost Enteric Coat
Eudragit~ S and dibutyl phthalate are dissolved in a solution of
isopropanol, acetone, and water (37:9:1 ) at levels of 8.0% and 1.6% {total
weight percent), respectively. Red ferric oxide and talc are then suspended
in the solution at levels of 1.2% and 2.1 % by weight, respectively. The
resulting mixture is coated onto the barrier coated substrates above in a
perforated pan coater maintaining an outlet air/bed temperature of about
30°
C.
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
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appended claims, all such modifications that are within the scope of this
invention.
