U.S. patent application number 10/672791 was filed with the patent office on 2004-04-08 for method of fabricating a banded prolonged release active agent dosage form.
Invention is credited to Edgren, David E., Jao, Francisco, Puga, Yolanda M., Wong, Patrick S.-L..
Application Number | 20040067300 10/672791 |
Document ID | / |
Family ID | 26771245 |
Filed Date | 2004-04-08 |
United States Patent
Application |
20040067300 |
Kind Code |
A1 |
Edgren, David E. ; et
al. |
April 8, 2004 |
Method of fabricating a banded prolonged release active agent
dosage form
Abstract
The present invention is directed to an active agent dosage form
and methods of its fabrication which is useful for the prolonged
delivery of an active agent formulation to a fluid environment of
use. The active agent dosage form is a matrix that has on its
surface one or more insoluble bands located in complementary
grooves. The invention is also directed to articles of manufacture,
methods and systems for fabricating the active agent dosage
form.
Inventors: |
Edgren, David E.; (El
Granada, CA) ; Wong, Patrick S.-L.; (Burlingame,
CA) ; Jao, Francisco; (San Jose, CA) ; Puga,
Yolanda M.; (Morgan Hill, CA) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
26771245 |
Appl. No.: |
10/672791 |
Filed: |
September 26, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10672791 |
Sep 26, 2003 |
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10076096 |
Feb 15, 2002 |
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10076096 |
Feb 15, 2002 |
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09274648 |
Mar 23, 1999 |
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6365183 |
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60084646 |
May 7, 1998 |
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Current U.S.
Class: |
427/2.14 |
Current CPC
Class: |
A61K 9/2095 20130101;
A61K 9/2893 20130101; A61K 9/2072 20130101 |
Class at
Publication: |
427/002.14 |
International
Class: |
A61J 001/00 |
Claims
What is claimed is:
1. A method of preparing an active agent dosage form for the
prolonged delivery of the active agent, comprising: forming a blank
from an active agent formulation matrix so that the blank has a
groove circumscribing a portion of the external surface of the
blank; and depositing insoluble material in the groove.
2. The method of claim 1, wherein said forming step comprises:
compressing the active agent formulation matrix; and embossing the
groove in the active agent formulation matrix so that it lies in a
plane perpendicular to the longitudinal axis of the blank.
3. The method of claim 1, wherein said depositing step comprises:
using printing means to transfer insoluble material into the
groove.
4. The method of claim 3, wherein the printing means comprises a
rotatable wheel.
5. The method of claim 4, wherein the wheel has a substantially
planar outer circumferential surface.
6. The method of claim 4, wherein the wheel has a concave outer
circumferential surface.
7. The method of claim 1, wherein said depositing step is carried
out so that the insoluble material does not extend above the
external surface of the blank.
8. The method of claim 1, further comprising: coating the blank
with a water-soluble film.
9. A method for fabricating an active agent dosage form for the
prolonged delivery of the active agent, comprising: providing a
blank, the blank comprising an active agent formulation matrix
having a groove circumscribing a portion of the external surface of
the blank; orienting the blank with respect to a forming means for
forming a band in the groove; and forming the band in the groove
using the forming means.
10. The method of claim 9, wherein said orienting step comprises:
registering the forming means with the groove.
11. The method of claim 10, wherein said registering step is
carried out using a rotatable wheel.
12. The method of claim 9, wherein said forming step comprises:
using printing means to transfer insoluble material into the
groove.
13. The method of claim 12, wherein the printing means comprises a
rotatable wheel.
14. The method of claim 13, wherein the wheel has a substantially
planar outer circumferential surface.
15. The method of claim 13, wherein the wheel has a concave outer
circumferential surface.
16. The method of claim 9, wherein said forming step is carried out
so that the band does not extend above the external surface of the
blank.
17. The method of claim 9, further comprising: coating the blank
with a water-soluble film.
18. The method of claim 9, further comprising: transporting the
blank from a source of blanks to the forming means.
19. An active agent dosage form for the prolonged delivery of an
active agent formulation to a fluid environment of use, comprising:
an active agent formulation matrix having a groove circumscribing a
portion of the external surface thereof; and an insoluble band
disposed in said groove.
20. The active agent dosage form of claim 19, wherein said groove
has a notch shape.
21. The active agent dosage form of claim 19, wherein said groove
has a concave shape.
22. The active agent dosage form of claim 19, wherein the depth of
said groove is between about 0.1 mm and about 3 mm.
23. The active agent dosage form of claim 19, wherein the width of
said groove is between about 0.5 mm and 10 mm.
24. The active agent dosage form of claim 19, further comprising: a
water-soluble film coating.
25. The active agent dosage form of claim 19, wherein the dosage
form comprises a plurality of grooves, each of said grooves
circumscribing a portion of the external surface of the active
agent formulation matrix.
26. The active agent dosage form of claim 25, wherein the dosage
form comprises an insoluble band disposed in each of said
grooves.
27. The active agent dosage form of claim 19, wherein said
insoluble band comprises a latex of acrylate polymers.
28. The active agent dosage form of claim 27, wherein said acrylate
polymers comprise copolymers of ethylacrylate and
methylmethacrylate.
29. The active agent dosage form of claim 27, wherein said latex
comprises an ethylacrylate methylmethacrylate 2:1 copolymer
latex.
30. A blank for formation of a pharmaceutical dosage form for
controlled delivery of an active agent, comprising: an active agent
formulation matrix having a groove circumscribing a portion of the
external surface of said matrix.
31. The blank of claim 30, wherein said groove has a notch
shape.
32. The blank of claim 30, wherein said groove has a concave
shape.
33. The blank of claim 30, wherein the depth of said groove is
between about 0.1 mm and about 3 mm.
34. The blank of claim 30, wherein the width of said groove is
between about 0.5 mm and 10 mm.
35. The blank of claim 30, wherein said active agent formulation
matrix has a cylindrical shape, the ends of which are rounded and
convex.
36. A system for fabricating an active agent dosage form for the
prolonged delivery of the active agent, comprising: forming means
for forming a band in a groove circumscribed on the external
surface of a blank; and orienting means for orienting, by way of
the groove, the blank with respect to said forming means.
37. The system of claim 36, wherein said orienting means comprises
means registering with the groove on the blank.
38. The system of claim 37, wherein said means registering with the
groove comprises a rotatable wheel.
39. The system of claim 36, wherein said forming means comprises: a
source of material for the band; and a printing wheel.
40. A system for fabricating an active agent dosage form for the
prolonged delivery of the active agent, comprising: a source of
blanks, each of said blanks having a groove circumscribing a
portion of the external surface of the blank; and a banding station
that forms a band of insoluble material in the groove.
41. The system of claim 40, wherein said banding station comprises:
a printing means.
42. The system of claim 41, wherein said printing means comprises:
a source of insoluble material; and a printing wheel.
43. The system of claim 42, wherein said printing wheel has a
substantially planar outer circumferential surface.
44. The system of claim 42, wherein said printing wheel has a
concave outer circumferential surface.
45. The system of claim 40, further comprising: a transport
mechanism that transports the blanks from said source to said
banding station.
46. The system of claim 45, wherein said transport mechanism
comprises: a stationary table; and a rotating transport table
adapted to rotate over said stationary table.
47. The system of claim 46, wherein said rotating transport table
defines a plurality of openings positioned linearly on respective
radii, said openings adapted to receive blanks from said
source.
48. The system of claim 40, further comprising: a drying apparatus
configured to dry the band.
Description
FIELD OF THE INVENTION
[0001] The present invention is related to the prolonged delivery
of an active agent. More particularly, it is directed to an
improved method of making a banded active agent dosage form which
is useful for delivering a beneficial agent to a fluid environment
of use.
BACKGROUND OF THE INVENTION
[0002] Tablets, capsules, caplets and many other types of devices
have been used for dispensing a beneficial agent to a fluid
environment of use. Easy manufacture of a device that provides for
prolonged delivery of an active agent in a controlled and
predictable manner continues to be a goal, especially in the area
of drug delivery.
[0003] U.S. Pat. No. 4,290,426 to Luschen et al describes a
cylindrical dispenser for releasing a beneficial agent into a fluid
environment at a rate that is governed by the fluid-induced
relaxation of a polymeric agent contained within the dispenser. The
cylindrical dispenser includes an impermeable container that has
within it a reservoir and a passageway from the reservoir to the
exterior of the container. The reservoir contains a polymer and a
beneficial agent. The polymer imbibes fluid from the environment
and thereby undergoes relaxation, releasing the beneficial agent
from the device. The amount of agent released is dependent on the
rate of relaxation of the polymer over time.
[0004] Coated dosage forms have also been suggested for delivery of
a controlled amount of a beneficial agent over a prolonged period
of time. U.S. Pat. No. 5,256,440 describes a process for producing
a film coated dosage form. A continuous groove is inscribed in a
dosage form core. A latex film is coated onto the core, the groove
defining a fixed zone and a detachable zone for the film. The
detachable portion of the latex film detaches when it is exposed to
the environment of use, thereby exposing a discrete portion of the
dosage form core surface. The remainder of the film remains
attached to the dosage form core. The exposed portion of the dosage
form surface erodes and releases active agent to the environment of
use.
[0005] Coated tablets for constant and prolonged drug release are
described by Conte et al in J. Controlled Release, Vol. 26, (1993)
pages 39-47. These GEOMATRIX.TM. Systems are swellable matrices
that are coated or tabletted with polymeric barrier layers. Release
performances of the systems are modulated as a result of the
restriction of the releasing surface by the polymeric barrier layer
coatings. As the extent of coating of the system's surface is
increased, the release kinetics of the system shift toward constant
release. These systems are further described in U.S. Pat. No.
4,839,177 to Colombo et al.
[0006] U.S. Pat. No. 5,534,263 describes a banded dosage form which
is useful for the sustained delivery of an active agent formulation
to a fluid environment of use. The active agent dosage form is a
matrix that has on its surface two or more insoluble bands. The
dosage form described provides significant advantages over other
prior art devices for the sustained delivery of an active
agent.
SUMMARY OF THE INVENTION
[0007] It has been observed that banded devices such as those
described in U.S. Pat. No. 5,534,263 ('263 patent), which is
incorporated herein by reference in its entirety, have significant
advantages for prolonged delivery of an active agent formulation to
a fluid environment of use. It has now been discovered that if the
active agent formulation matrix is provided with at least one
groove, prior to the banding process described in the '263 patent,
the groove can be used as a register to orient the dosage form
during the banding process. Additionally, the groove allows for
more uniform deposition of the banding material. In that manner,
improved dosage forms are provided and savings and manufacturing
advantages are achieved.
[0008] Accordingly, the present invention is directed to an
improved method and system for manufacturing banded dispensing
devices, to improved articles of manufacture, and to components
that facilitate manufacture of the devices.
[0009] In one aspect, the invention comprises an active agent
dosage form for the prolonged delivery of an active agent
formulation to a fluid environment of use, the dosage form
comprising an active agent formulation matrix having at least one
groove circumscribing a portion of the surface thereof and an
insoluble band positioned in the groove.
[0010] In another aspect the invention comprises a blank for
formation of an active agent dosage form for controlled delivery of
an active agent, the blank comprising an active agent formulation
matrix having at least one groove circumscribing a portion of the
surface thereof.
[0011] In a further aspect the invention comprises a banding system
for fabricating an active agent dosage form comprising means for
orienting a blank having a groove and means for forming a band in
the groove.
[0012] The invention comprises the following characteristics and
features, either alone or in combination with one or more of each
other.
[0013] An active agent dosage form for the prolonged delivery of an
active agent formulation to a fluid environment of use, the dosage
form comprising an active agent formulation matrix having at least
one groove circumscribing a portion of the surface thereof and an
insoluble band located in the groove; the dosage form wherein the
groove has the shape of a notch; the dosage form wherein the groove
has a continuous concave shape; the dosage form wherein the depth
of the groove is between 0.1 and 3 mm; the dosage form wherein the
width of the groove is between 0.5 and 10 mm; the dosage form
wherein the outer surface and bands are coated to form a smooth,
exterior surface; and the dosage form having more than one groove
circumscribing a portion of the surface thereof and an insoluble
band located in each groove.
[0014] A blank for formation of a pharmaceutical dosage form for
controlled delivery of an active agent, the blank comprising an
active agent formulation matrix having at least one groove
circumscribing a portion of the surface thereof, the blank wherein
the groove has the shape of a notch; the blank wherein the groove
has a continuous concave shape; the blank wherein the depth of the
groove is between 0.1 and 3 mm; the blank wherein the width of the
groove is between 0.5 and 10 mm; the blank wherein the groove
functions as a location register, the blank wherein the groove is
adapted to cooperate with a printing means; the blank wherein the
groove is adapted to cooperate with a printing means having a latex
source; and the blank wherein the groove is adapted to cooperate
with a printing means having a latex source selected from acrylate
esters.
[0015] A system for fabricating the dosage form from a blank
comprising an active agent formulation matrix and at least one
groove on the surface thereof, the system comprising means for
orienting the blank by means of a groove in the blank, and means
for forming a band in a groove; the system including means for
transporting the blank; the system wherein the means for orienting
the blank includes means registering with one or more of the
grooves on the blank; the system wherein the means for orienting
the blank includes a rotatable wheel; the system wherein the band
forming material comprises a latex of acrylate polymers; the system
wherein the acrylate polymers comprise copolymers of ethylacrylate
and methylmethacrylate; and the system wherein the means for
forming a band in a groove comprises printing means.
[0016] A method of preparing an active agent dosage form for the
prolonged delivery of an active agent formulation to a fluid
environment of use, the dosage form comprising an active agent
formulation matrix having at least one groove circumscribing a
portion of the surface thereof and a band of insoluble material
positioned in the groove, the method comprising forming a blank
having a groove corresponding to a desired location of the
insoluble band, and coating the groove with the insoluble
material.
DESCRIPTION OF THE DRAWINGS
[0017] The figures are not drawn to scale, but are set forth to
illustrate various embodiments of the invention. Like numbers refer
to like structures.
[0018] FIG. 1 is a side elevational view of one embodiment of a
blank useful for fabrication of the delivery device of the present
invention, the blank being in prepared form prior to printing of
bands in the grooves on the surface of the blank.
[0019] FIG. 2 illustrates the blank of FIG. 1 after the banding
operation has been completed.
[0020] FIG. 3 is a side elevational view illustrating a particular
embodiment of the blank of this invention having a groove formed as
a concave surface.
[0021] FIG. 4 illustrates the blank of FIG. 3 after the banding
operation has been completed.
[0022] FIG. 5 is a side elevational view illustrating another
embodiment of a blank of this invention having a groove formed as a
notch.
[0023] FIG. 6 illustrates the blank of FIG. 5 after the banding
operation has been completed.
[0024] FIG. 7 is a side, elevational view schematically
illustrating the major components of the banding system of the
present invention.
[0025] FIG. 8 is a top view of the banding system illustrated in
FIG. 7, the tablet drying means not being shown.
[0026] FIG. 9 is an illustration of one embodiment of the printing
station in the banding means of the invention with a printing wheel
having a substantially planar printing surface.
[0027] FIG. 10 is an illustration of an alternate embodiment of the
printing station in the banding means of the invention with a
printing wheel having a concave printing surface.
[0028] FIG. 11 is a perspective view of a typical blank of this
invention formed from horizontal compression in a tabletting
press.
DETAILED DESCRIPTION OF THE INVENTION
[0029] The present invention provides a delivery device and
articles of manufacture and. systems and methods for fabrication of
the device, the device being useful for the prolonged delivery of
an active agent formulation to a fluid environment of use.
DEFINITIONS
[0030] The phrase "prolonged delivery" intends a period of delivery
that lasts for several hours to about 24 hours, usually up to about
20 hours, and often between about 3 and 16 hours.
[0031] By "insoluble" is intended a material that will not
dissolve, degrade or erode in the environment of use during the
delivery period.
[0032] By "apply" or "applied" or "application" is intended the
deposition of insoluble material, in liquid or in molten form, onto
the active agent formulation matrix. A variety of techniques may be
used to apply the insoluble material, including but not limited to
Gravure-type printing, extrusion coating, screen coating, brush
coating, spraying, painting, and the Capsealer process developed by
TAIT Design & Machine Co., Manheim, Pa. and the system
developed and sold by Shionogi Qualicaps of Indianapolis, Ind.,
commonly referred to as the Quali-seal.TM. process. These systems
can be used with modification of their usual capsule feed systems
to accommodate the compressed tablet blanks typically used in the
present invention.
[0033] The term "active agent formulation" intends the active agent
or drug optionally in combination with pharmaceutically acceptable
carriers and additional inert ingredients.
[0034] The term "active agent formulation matrix", as used herein,
comprises the active agent formulation in combination with a
hydrophilic polymeric material.
[0035] The "active agent dosage form" intends the active agent
formulation matrix as defined above with one or more bands of an
insoluble material applied onto its surface.
[0036] The term "blank" means an active agent formulation matrix
formed without any band but with at least one groove circumscribing
a portion of its surface. A blank may have more than one groove to
facilitate placement of a plurality of bands contemplated
herein.
[0037] As used herein, the terms "therapeutically effective" amount
or rate refer to the amount or rate of the active agent needed to
effect the desired pharmacologic, often beneficial, result.
[0038] The dispensing devices of the invention embody improvements
over the dispensing devices described in U.S. Pat. No. 5,534,263
("263 patent"), which is incorporated herein by reference. The
dispensing devices of the invention find use, for example, in
humans or other animals. The environment of use is a fluid
environment and can comprise the stomach, the intestinal tract, or
a body cavity such as the peritoneum or vagina. A single dispensing
device or several dispensing devices can be administered to a
subject during a therapeutic program.
[0039] The dispensing devices of the invention are fabricated by
methods and with systems improved over that described in the '263
patent and the prior art. In prior methods, the dispensing devices
were produced from cylindrical tablets having a uniformly
continuous external surface without any grooves. In the banding
equipment unbanded tablets were rotated at a printing station as
banding material was applied to the external surface of the
unbanded tablets. Bands were thus applied to the external surface
and the band thickness resulted in a finished banded device having
a non-uniform external surface as can be seen from the
illustrations in the figures of the '263 patent. The unbanded
tablets were rotated independently of the printing means and had
the tendency to wobble as the bands were applied. This resulted in
some of the bands being applied in a non-uniform manner,
particularly around the edges, and with non-uniform band thickness.
Such non-uniformity may affect the delivery profile of the active
agent from the dispensing device and, as such, a less than optimal
delivery device is produced.
[0040] It has now been discovered that if an indexing or register
means is provided on the unbanded device prior to the banding
operation, the banding means can be configured to cooperate with
the indexing or register means to locate the unbanded device
accurately at the location at which the insoluble band material is
placed on the unbanded device during the banding operation. The
indexing or register means may be provided by one or more grooves,
formed on a portion of the external surface of the unbanded device,
that cooperate with the banding means. Accordingly, bands can be
applied with greater uniformity in location, width and thickness.
This results in rejection of fewer dispensing devices for being out
of specifications and also provides dispensing devices having
optimal surface characteristics and active agent release profiles.
The indexing or register means cooperates with the banding means to
align the unbanded dispensing device during the banding
operation.
[0041] The invention can best be understood with reference to the
drawings.
[0042] FIG. 1 depicts, in side elevational view, one embodiment of
the unbanded dispensing device, which henceforth will be referred
to as a "blank". The blank is shown in prepared form prior to
placement of the bands. Blank 1 is shown in FIG. 1 to comprise a
cylindrically shaped active agent formulation matrix 12. The ends
14 and 16 of the matrix are preferably rounded and convex in shape
in order to ensure ease of insertion into the environment of use.
Grooves 20, 22 and 24 are formed in and circumscribe the exterior
surface of the active agent formulation matrix 12. Multiple grooves
are illustrated. However, it will be appreciated that the blank may
be formed with only one groove or with more than one groove.
[0043] FIG. 2 shows blank 1 after the banding operation has been
completed and bands 30, 32, and 34 have been formed in grooves 20,
22, and 24, respectively. That operation results in a delivery
device that is suitable to be placed in the fluid environment of
use and operate as described in the '263 patent. Because the bands
have been placed in the grooves and generally will be configured to
extend only to the outer surface of the blank, the outer surface of
the delivery device will be quite smooth. Optionally, however, the
completed device may be coated with a water-soluble film as
described in the '263 patent. The active agent formulation matrix
12 between bands 30, 32 and 34 and at its ends 14 and 16 will erode
when the delivery device is placed in the environment of use,
thereby releasing active agent to the fluid environment of use.
[0044] FIG. 3 shows a blank 1 having a single groove 44, shaped as
a concave surface, in the outer surface of active agent formulation
matrix 42. While a single groove is illustrated, more than one
groove may be provided depending on the number of bands that will
be placed on the completed delivery device.
[0045] FIG. 4 shows blank 1 after the banding operation has been
completed to form a completed delivery device. Groove 44 has been
imprinted with band 46, which, as illustrated, has to some extent
assumed the concave shape of groove 44. However, it is to be
understood that band 46 may be formed with additional material to
fill groove 44 to provide an external surface in the area of the
groove that is level with the external surface of the active agent
formulation matrix 42 outside of the banded area. As has been
described previously, the banded dispensing device may be used in
that configuration, or it may be optionally over-coated with a
water-soluble film as described in the '263 patent. When placed in
the environment of use, any optional over-coated water soluble film
will dissolve, and the external surface of active agent matrix 42
not covered by band 46 will erode and release active agent. Erosion
will continue and the exposed ends will separate from the banded
portion of the device. Upon continued erosion, band 46 will
separate from any remaining active agent formulation matrix and
will thereafter be expelled from the fluid environment of use.
[0046] FIG. 5 shows another embodiment of a blank 1 of the
invention having a notched groove 54 formed with sloping sides 56.
It is to be appreciated that sides 56 could be formed at other
angles to the longitudinal axis of the active agent formulation
matrix 52. For example, sides 56 could be at right angles to the
longitudinal axis. The particular choice of shape will be made by
one skilled in the art depending on application for which the
dispensing device is intended to be used.
[0047] FIG. 6 shows the blank of FIG. 5 after the banding operation
has been completed and a band 58 has been located in groove 54. The
notched shape facilitates the application of a uniform thickness of
material forming band 58, and may provide an external surface that
is level with the surface of the active agent formulation matrix
52. More than one groove 54 can be provided as desired. The blank
and delivery device can be utilized as described herein and in
accordance with the teachings of the '263 patent.
[0048] The number, size, and placement of the insoluble bands that
are applied onto the active agent formulation matrix may be varied
to provide a desired drug delivery profile, in conjunction with
design of the active agent formulation. For example, grooves of
from about 0.1 mm to about 12 mm in width, preferably between about
0.5 and 10 mm, and most preferably between about 0.5 and 8 mm, may
be formed into the blank, resulting in bands of approximately that
width on the active agent formulation matrix surface. Typically,
the grooves will be formed with a maximum depth of 0.1 mm to 3 mm,
preferably 0.1 mm to 2 mm. However, for applications where there is
significant swelling of the polymer matrix of the tablet, the depth
of the groove may be greater to accommodate bands of increased
thickness and strength. Between about 1 and 10 bands may be used,
but generally between about 1 and 6 are affixed to the matrix. The
bands may be placed close together (i.e., within about 0.5 mm of
each other) or may be placed at opposite ends of the matrix (i.e.,
spaced about 8 to 12 mm apart).
[0049] The insoluble material may be any material that is nontoxic,
biologically inert, nonallergenic and nonirritating to body tissue,
and that maintains its physical and chemical integrity; that is,
the bands do not erode or degrade in the environment of use during
the dispensing period. Insoluble materials from which the bands may
be prepared include, for example, polyethylene, polystyrene,
ethylene-vinyl acetate copolymers, polycaprolactone and Hytrel.RTM.
polyester elastomers (Du Pont). Additional banding materials
include but are not limited to polysaccharides, cellulosics,
powdered cellulose, microcrystalline cellulose, cellulose acetate,
cellulose acetate pseudolatex (such as described in U.S. Pat. No.
5,024,842), cellulose acetate propionate, cellulose acetate
butyrate, ethyl cellulose, ethyl cellulose pseudolatex (such as
Surelease.RTM. as supplied by Colorcon, West Point, Pa. or
Aquacoat.TM. as supplied by FMC Corporation, Philadelphia, Pa.),
nitrocellulose, polylactic acid, poly-glycolic acid, polylactide
glycolide copolymers, collagen, polycaprolactone, polyvinyl
alcohol, polyvinyl acetate, polyethylene vinylacetate, polyethylene
teraphthalate, polybutadiene styrene, polyisobutylene,
polyisobutylene isoprene copolymer, polyvinyl chloride,
polyvinylidene chloride-vinyl chloride copolymer, copolymers of
acrylic acid and methacrylic acid esters, copolymers of
methylmethacrylate and ethylacrylate, latex of acrylate esters
(such as Eudragit.RTM. supplied by RohmPharma, Darmstaat, Germany),
polypropylene, copolymers of propylene oxide and ethylene oxide,
propylene oxide ethylene oxide block copolymers, ethylenevinyl
alcohol copolymer, polysulfone, ethylene vinylalcohol copolymer,
polyxylylenes, polyamides, natural and synthetic waxes, paraffin,
carnauba wax, petroleum wax, white or yellow bees wax, castor wax,
candelilla wax, rice bran wax, microcrystalline wax, stearyl
alcohol, cetyl alcohol, bleached shellac, esterified shellac,
chitin, chitosan, silicas, polyalkoxysilanes, polydimethyl
siloxane, polyethylene glycol-silicone elastomers, crosslinked
gelatin, zein, electromagnetic irradiation crosslinked acrylics,
silicones, or polyesters, thermally crosslinked acrylics,
silicones, or polyesters, butadiene-styrene rubber, glycerol ester
of partially dimerized rosin, glycerol ester of partially
hydrogenated wood rosin, glycerol ester of tall oil rosin, glycerol
ester of wood rosin, pentaerythritol ester of partially
hydrogenated wood rosin, pentaerythritol ester of wood rosin,
natural or synthetic terpene resin and blends of the above.
[0050] Preferred banding materials include copolymers of acrylic
acid and methacrylic acid esters, copolymers of methylmethacrylate
and ethylacrylate, and latex of acrylate esters. Preferred
copolymers include poly (butyl methacrylate,
(2-dimethylaminoethyl)methacrylate, methyl methacrylate) 1:2:1,
150,000, sold under the trademark EUDRAGIT E; poly (ethyl acrylate,
methyl methacrylate) 2:1, 800,000, sold under the trademark
EUDRAGIT NE 30 D; poly (methacrylic acid, methyl methacrylate) 1:1,
135,000, sold under the trademark EUDRAGIT L; poly (methacrylic
acid, ethyl acrylate) 1:1, 250,000, sold under the trademark
EUDRAGIT L; poly (methacrylic acid, methyl methacrylate) 1:2,
135,000, sold under the trademark EUDRAGIT S; poly (ethyl acrylate,
methyl methacrylate, trimethylammonioethyl methacrylate chloride)
1:2:0.2, 150,000, sold under the trademark EUDRAGIT RL; poly (ethyl
acrylate, methyl methacrylate, trimethylammonioethyl methacrylate
chloride) 1:2:0.1, 150,000, sold as EUDRAGIT RS. In each case, the
ratio x:y:z indicates the molar proportions of the monomer units
and the last number is the number average molecular weight of the
polymer. An ethylacrylate methylmethylacrylate 2:1 copolymer latex
is especially preferred.
[0051] The banding materials often are also formulated with
plasticizers, and optionally with wetting agents, surfactants,
opacifiers, colorants, flavorants, taste-masking agents, and the
like. Examples of typical plasticizers are as follows: polyhydric
alcohols, triacetin, polyethylene glycol, glycerol, propylene
glycol, acetate esters, glycerol triacetate, triethyl citrate,
acetyl triethyl citrate, glycerides, acetylated monoglycerides,
oils, mineral oil, castor oil and the like. Triacetin presently is
a preferred plasticizer. The plasticizers may be blended into the
latex in amounts of 10-50 weight percent based on the weight of the
latex. Preferably, 20-40 weight percent of plasticizer, based on
the weight of the latex, may be utilized.
[0052] Tablets formed of the active agent formulation matrix are
made by standard granulation and tabletting methods. The tablet
tooling however is of particular design; it is made for use in the
horizontal compression mode ("HCT"), such as described, for
example, in Remington's Pharmaceutical Sciences, 14th Edition,
pages 1660-1666. Tableting design is described in Pharmaceutical
Dosage Forms: Tablets, Volume 2, Chapter 7, published by Marcel
Dekker, Inc. Tooling is designed with embossment to form one or
more grooves in the active agent formulation matrix as it is
tabletted. The HCT tablets are compressed such that at least one
continuous groove is embossed which lies in a plane perpendicular
to the longitudinal axis of the tablet and circumscribes a portion
of the external surface of the tablet. Dies and punches are
fabricated with ridges that are located, shaped and sized to form
the grooves in the blanks as the active agent formulation matrix is
tabletted.
[0053] Fabrication of the completed delivery devices by banding the
blanks of the invention may take place on tablet or caplet banding
systems and in accordance with known banding processes as described
generally below.
[0054] The grooved tablets formed in the tabletting operation are
fed to a banding machine (Tait or Shinonogi capsealer). The tablets
roll on the machine and when they reach the banding station, the
printing wheel(s) transfers coating material (e.g., ethylacrylate
methylmethacrylate 2:1 copolymer latex) into the groove(s).
Typically, one printing wheel corresponding to each groove on the
blank will be used. The width of the wheels is smaller than the
width of the grooves so that the printing surface of the wheel
rotates within the confines of the groove. The system continues to
rotate while the water of the latex is subsequently dried in a
current of warm air. The bands form within the grooves as the water
is removed and the latex coalesces. The system is optionally given
a final film overcoat to complete fabrication, as is described in
the '263 patent. Bands of the resulting systems have clean,
straight borders, defined by the borders of the embossed grooves
and uniform thickness. Typically, the band edges will meet, or at
least do not extend above, the external surface of the active agent
formulation matrix, thus providing a smooth, continuous outer
surface. While the invention is described with the printing means
comprising a printing wheel for application of the banding material
to the groove surface, it is understood that other printing
apparatus known to those skilled in the art, such as jet-droplet
printing, offset Gravure equipment, spray curtain printing, and the
like, may be used as well.
[0055] A schematic of a banding system useful in the practice of
the invention is illustrated in greater detail in FIGS. 7-10. As
shown, the banding system comprises a source of blanks, typically a
vibratory or rotary feed hopper 61; a transport mechanism to move
blanks to the printing station, typically comprising a rotating
transport table 62, or alternatively a linear conveyer, and a
stationary table 63 upon which the blanks roll during processing;
and one or more banding stations 64 having a printing means,
typically including a source of banding material 65 and a printing
wheel 66.
[0056] In the illustrated embodiment, the feed hopper 61 is
positioned over table 62 that is adapted to rotate horizontally
over stationary table 63. Table 62 is formed with a plurality of
slots or openings 67 that are positioned linearly on respective
radii of table 62 and are adapted to receive blanks from the feed
hopper. For ease of illustration, a single feed hopper that feeds a
plurality of slots 67 along a radius of table 62 is shown.
Alternatively, individual feed hoppers for each circumferential set
of openings might be used. Table 63 forms a stationary surface that
supports the blanks as the blanks are transported to banding
station 64. Openings 68, shown in FIGS. 9 and 10, in stationary
table 63 are sized to be slightly smaller than openings 67 so that
the blanks continue to be supported at the banding station.
Openings 68 are sized to accommodate the printing means so that
banding material can be applied to the grooves of the blank.
[0057] Located above table 62 is a drying apparatus, indicated
generally as 69. Drying apparatus 69 may be of conventional design,
including, for example, a fan for forcing ambient air over a heater
element to warm the air, which is then directed with appropriate
ducting to the area of table 62 in which banded tablets are
located. The banded tablets will continue to rotate because of the
rotation of table 62 over stationary table 63 and be dried as they
pass through the warm-air environment provided by the drying
apparatus 69. While a single drying apparatus at a single drying
station is shown, it will be understood that multiple units may be
used if necessary to complete the drying of the banded tablets in a
single cycle of rotation of table 62. In some circumstances,
particularity, where relatively thicker bands are deposited on the
blanks, a first drying apparatus may provide an initial amount of
drying at a lower temperature to prevent too rapid drying of the
banding material, and one or more additional drying apparatuses may
provide additional drying cycles at a higher temperature to
complete final drying of the banded tablets.
[0058] Table 63 is formed with a second set of openings or a
continuous slot (not shown) extending along a radius of table 63
through which banded tablets may be released from the slots 67 into
a collection apparatus.
[0059] As table 62 rotates above the stationary surface of table
63, the blanks rotate about their longitudinal axes as they are
transported to the banding station. Although only a single printing
wheel 66 is shown for illustration purposes, it is to be understood
that a plurality of printing wheels may be provided along a radius
of table 62 under openings 67 so that each blank will be
appropriately banded as it reaches the banding station. In that
manner, each of the blanks positioned within openings 67 along a
particular radius of table 62 may be banded at the same time. In
those instances where blanks having a plurality of grooves are to
be banded, it will usually be most efficient to provide multiple
printing wheels equal to the number of grooves at each banding
station so that each of the grooves may be banded simultaneously.
If it is desired, a similar banding station may be positioned at
another set of openings 67 in table 63 along other radii, thus
providing the opportunity to apply additional banding material to
the banded blanks if thicker coatings or coatings of different
compositions are desired.
[0060] As shown in FIGS. 9 and 10, the grooves formed on the blanks
of the invention act as an indexing or register means to cooperate
with the printing means in the fabrication system and at the same
time provide dispensing devices having the desired release profile
of active agent. With reference to FIG. 9, blank 1 is shown at a
location above a printing wheel 66. Groove 20 is indexed by and
registers with banding wheel 66. The outer circumferential surface
of banding wheel 66 may be a generally planar surface 71 as shown
in FIG. 9, or it may be a concave surface 72 as shown in FIG. 10.
The concave surface is usually employed if thicker bands are
required to obtain the desired release profile of the active agent,
since the concave surface permits the application of a greater mass
of banding material in a single application than is possible with
the flat surface. The printing surface of printing wheel 66 may
optionally be smooth or rough depending upon the application
intended. A rough surface can consist of a knurled surface, a
sandblasted or pebbled surface, or a matte finish. The purpose of
the roughened printing surface is to promote frictional contact to
the blank as the blank rotates over printing wheel 66 to enhance
rotation with improved traction. Another purpose of the roughened
surface is to increase the application rate of banding material 65
by increasing the amount of banding material transferred from the
band feed source per each rotation of the printing wheel. The
printing surface of the printing wheel can also be configured with
one or more channels to facilitate efficient transfer of the
banding material from the feed source to the blank. An end-on view
of such a printing wheel with a single channel 72 is illustrated in
FIG. 10. The edges 73 and 74 forming the channel may be smooth or
roughed as discussed previously with respect to the planar surface
of printing wheel 66. As printing wheel 66 rotates through the
banding material, it picks up banding material on its
circumferential surface and deposits it onto the surface of groove
20. The rate of rotation of table 62 is adjusted to provide a
residence time for the blanks at the banding station that is
adequate to allow for application of the desired amount of banding
material. Typically, table 62 will rotate in a range of 0.25 to 2.1
revolutions per minute (rpm) and printing wheel 66 will rotate in a
range of 15 to 120 rpm. For most typical applications, table 62
preferably rotates between 0.5 and 0.75 rpm, most preferably
between 0.6 and 0.7 rpm, and printing wheel 66 preferably rotates
between 30 and 60 rpm, most preferably between 40-50 rpm.
[0061] The grooves in the blanks additionally act as templates for
the formation of bands on the dosage forms, thus facilitating
control of the width, depth, location and edge characteristics of
the bands. Also, banded dosage forms having a smooth, outer surface
can be produced with or without coating of an overlayer on the
banded tablet.
[0062] Fabrication of expandable dosage forms, for example, those
intended for gastric retention, follows a similar procedure. In
this case, the groove which circumscribes the tablet may be either
shallow or deep. However, if the dosage form is intended to expand
significantly from uptake of fluid (e.g. 100% to 500% of its dry
volume), deeper grooves usually will be employed. In the
deep-groove configuration, the shape of the groove can be in the
form of a notch or a saddle point (FIGS. 3-6). The diameter of the
tablet at these deep-grooved areas is smaller than the tablet
diameter overall. Therefore, when this core is banded at a fixed
wheel rotation speed and fixed dwell time, a thicker band can form
within the groove than would be formed without the groove. Thick,
robust rings are needed when the gastric retention system is in
operation to withstand the pressure generated by high-swelling
fibers and hydrogels of the core as the system enlarges to
dimensions larger than the pylorus. Typically, deep-grooved rings
will have a maximum depth of from about 0.5 mm to about 3 mm,
although it is understood that the thickness may be less or greater
as selected by one skilled in the art for the particular
application at hand.
[0063] FIG. 11 illustrates a typical blank 1 formed with a groove
20 from horizontal compression of the bulk active agent
formulation. In contrast to conventional gelatin capsules that have
a smooth outer surface and are generally of circular cross-section,
a horizontally compressed blank may have a number of surfaces, such
as the land area designated 75 and surfaces 76 and 77, that impart
some non-circular irregularity to the cross-section of the tablet.
Application of the banding material according to the process of the
present invention typically will cover those surfaces with banding
material to provide a smooth surface after banding. To the extent
that the land area outside of the groove is not covered by banding
material, the banded tablet may be overcoated as described
previously to provide for a smooth, outer surface.
[0064] The active agent of the active agent formulation may be in
liquid, solid or semisolid form. The active agent formulation may
contain additional materials and may be designed in a multitude of
ways to provide a specific drug delivery profile. One embodiment
comprises a formulation that contains a biologically acceptable
hydrophilic polymer which is capable of slow dispersion in the
environmental fluid. In another embodiment, the formulation may
contain a hydrophilic polymer and a surfactant so that the
formulation is susceptible to erosion in the environment. In still
another embodiment, the formulation may include a solid surfactant
so that the formulation is susceptible to erosion in the
environment. In still another embodiment, the formulation may
include a solid surfactant and provide drug delivery in a finely
dispersed form. In yet a further embodiment, the formulation may
include coated microspheres of an active agent and an adjuvant. The
active agent and adjuvant can be delivered simultaneously from the
microspheres either by diffusion or by osmosis. Suitable materials
useful as active agent carriers and excipients are known in the art
and are disclosed in U.S. Pat. Nos. 4,595,583 and 4,874,388, for
example.
[0065] The terms "active agent" and "drug" are used interchangeably
herein and refer to an agent, drug, compound, composition of matter
or mixture thereof which provides some pharmacologic, often
beneficial, effect. This includes pesticides, herbicides,
germicides, biocides, algicides, rodenticides, fungicides,
insecticides, antioxidants, plant growth promoters, plant growth
inhibitors, preservatives, antipreservatives, disinfectants,
sterilization agents, catalysts, chemical reactants, fermentation
agents, foods, food supplements, nutrients, cosmetics, drugs,
vitamins, sex sterilants, fertility inhibitors, fertility
promoters, microorganism attenuators and other agents that benefit
the environment of use. As used herein, the terms further include
any physiologically or pharmacologically active substance that
produces a localized or systemic effect or effects in animals,
including warm blooded mammals, humans and primates; avians; dom
stic household or farm animals such as cats, dogs, sheep, goats,
cattle, horses and pigs; laboratory animals such as mice, rats and
guinea pigs; fish; reptiles; zoo and wild animals; and the like.
The active drug that can be delivered includes inorganic and
organic compounds, including, without limitation, drugs which act
on the peripheral nerves, adrenergic receptors, cholinergic
receptors, the skeletal muscles, the cardiovascular system, smooth
muscles, the blood circulatory system, synoptic sites,
neuroeffector junctional sites, endocrine and hormone systems, the
immune system, the reproductive system, the skeletal system,
autacoid systems, the alimentary and excretory systems, the
histamine system and the central nervous system. Suitable agents
may be selected from, for example, proteins, enzymes, hormones,
polynucleotides, nucleoproteins, polysaccharides, glycoproteins,
lipoproteins, polypeptides, steroids, hypnotics and sedatives,
psychic energizers, tranquilizers, anticonvulsants, muscle
relaxants, antiparkinson agents, analgesics, antiepileptics,
antibiotics, anti-inflammatories, local anesthetics, muscle
contractants, antimicrobials, antivirals, antimalarials, hormonal
agents including contraceptives, sympathomimetics, polypeptides and
proteins capable of eliciting physiological effects, diuretics,
lipid regulating agents, antiandrogenic agents, antiparasitics,
neoplastics, antineoplastics, hypoglycemics, nutrional agents and
supplements, growth supplements, fats, ophthalmics, antienteritis
agents, electrolytes and diagnostic agents.
[0066] Examples of beneficial agents useful in this invention
include prochlorperazine edisylate, ferrous sulfate, aminocaproic
acid, mecamylamine hydrochloride, procainamide hydrochloride,
amphetamine sulfate, methamphetamine hydrochloride, benzphetamine
hydrochloride, isoproterenol sulfate, phenmetrazine hydrochloride,
bethanechol chloride, methacholine chloride, pilocarpine
hydrochloride, atropine sulfate, scopolamine bromide, isopropamide
iodide, tridihexethyl chloride, performing hydrochloride,
methylphenidate hydrochloride, theophylline cholinate, cephalexin
hydrochloride, diphenidol, meclizine hydrochloride,
prochlorperazine maleate, phenoxybenzamine, thiethylperazine
maleate, anisindione, diphenadione erythrityl tetranitrate,
digoxin, isoflurophate, acetazolamide, methazolamide,
bendroflumethiazide, phenytoin,minocycline, acyclovir, ganciclovir,
fenoxadine, chlorpropamide, tolazamide, chlormadinone acetate,
phenaglycodol, allopurinol, aluminum aspirin, fexofenadine,
methotrexate, acetyl sulfisoxazole, hydrocortisone,
hydrocorticosterone acetate, cortisone acetate, dexamethasone and
its derivatives such as betamethasone, triamcinolone,
methyltestosterone, 17-.beta.-estradiol, ethinyl estradiol, ethinyl
estradiol 3-methyl ether, prednisolone,
17-.beta.-hydroxyprogesterone acetate, 19-nor-progesterone,
norgestrel, norethindrone, norethisterone, norethiederone,
progesterone, norgesterone, norethynodrel, aspirin, acetaminophen,
indomethacin, naproxen, fenoprofen, sulindac, indoprofen,
nitroglycerin, isosorbide dinitrate, propranolol, timolol,
atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa,
chlorpromazine, methyidopa, dihydroxyphenylalanine, calcium
gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin,
haloperidol, zomepirac, ferrous lactate, vincamine,
phenoxybenzamine, diltiazem, milrinone, captropril, mandol,
quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen,
fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuninal,
nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine,
lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine,
lisinopril, enalapril, captopril, ramipril, enalaprilat,
famotidine, nizatidine, sucralfate, etintidine, tetratolol,
minoxidil, chlordiazepoxide, diazepam, amitriptyline, and
imipramine. Further examples are proteins and peptides which
include, but are not limited to, insulin, colchicine, glucagon,
thyroid stimulating hormone, parathyroid and pituitary hormones,
calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone,
follicle stimulating hormone, chorionic gonadotropin, gonadotropin
releasing hormone, bovine somatotropin, porcine somatropin,
oxytocin, vasopressin, prolactin, somatostatin, lypressin,
pancreazymin, luteinizing hormone, LHRH, interferons, interleukins,
growth hormones such as human growth hormone, bovine growth hormone
and porcine growth hormone, fertility inhibitors such as the
prostaglandins, fertility promoters, growth factors, and human
pancreas hormone releasing factor.
[0067] It is to be understood that more than one active agent may
be incorporated into the active agent formulation in a device of
this invention, and that the use of the term "agent" or "drug" in
no way excludes the use of two or more such agents or drugs.
[0068] The agents can be in various forms, such as uncharged
molecules, components of molecular complexes or nonirritating,
pharmacologically acceptable salts. Also, simple derivatives of the
agents (such as ethers, esters, amides, etc) which are easily
hydrolyzed by body pH, enzymes, etc, can be employed.
[0069] The amount of active agent employed in the delivery device
will be that amount necessary to deliver a therapeutically
effective amount of the agent to achieve the desired result at the
site of delivery. In practice, this will vary widely depending upon
the particular agent, the site of delivery, the severity of the
condition, and the desired therapeutic effect. Thus, it is not
practical to define a particular range for the therapeutically
effective amount of active agent incorporated into the device.
[0070] The hydrophilic polymeric material useful herein may
comprise, polysaccharides, methyl cellulose, sodium or calcium
carboxymethyl cellulose, nitrocellulose, carboxymethyl cellulose
and other cellulose ethers, and polyethylene oxides (e.g.,
Polyox.RTM., Union Carbide). Other materials useful as the
hydrophilic polymeric material include but are not limited to
hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl
ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate,
cellulose butyrate, cellulose propionate, cellulose fibers,
gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl
pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty
acid esters, polyacrylamide, polyacrylic acid, sodium and potassium
salts of polyacrylic acid, copolymers of ethacrylic acid or
methacrylic acid (Eudragit.TM.) or other acrylic acid derivatives,
sorbitan esters, natural gums, lecithins, pectin, alginates,
ammonia alginate, sodium or potassium alginate, calcium alginate,
propylene glycol alginate, potassium alginate, agar, gum arabic,
gum karaya, locust bean gum, gum tragacanth, carrageenans, gum
ghatti, guar gum, xanthan gum, scleroglucan, and blends of the
above.
[0071] The pharmaceutically acceptable carrier useful herein may
comprise more than one ingredient, such as, for example, a buffer,
a viscosity regulating vehicle, a surfactant, a dye, a permeation
enhancer, a proteinase inhibitor, or other formulation ingredients
and additives, as are known in the art.
[0072] The rate of release of the active agent from the active
agent dosage forms is predominantly controlled by erosion of the
aqueous gel formed by contacting the matrix with the fluid
environment of use.
[0073] The rate of active agent released from a cylindrical dosage
form without bands versus time will continuously decrease with
time. As drug is released from an unbanded capsule, the diameter of
the cylinder as well as the area of erosion decreases. In contrast,
as the polymeric core of the banded cylinder of this invention
shrinks, new surface area is created and exposed to the environment
of use as described in greater detail in the '263 patent. As a
result, the amount of active agent released over time may remain
constant or may increase with time depending on the rate of the new
surface area being generated. By arrangement of the number, size
and location of bands on the dosage form, the total new surface
area created by erosion can be predicted and the desired release
profile can be achieved.
[0074] The bands may be placed onto the surface of the matrix such
that, as the matrix erodes, the bands become loose and drop off the
matrix. These bands are easily excreted from the gastrointestinal
tract. As the number of bands remaining on the surface of the
matrix decreases, more matrix surface area will be exposed. The
matrix will therefore erode in a fashion that approaches zero order
rate.
[0075] In order to prepare a device of the present invention, the
active agent formulation is first prepared and formed into a blank
of the desired size and shape and having the desired number of
grooves with the desired groove shape. The matrix in its initial
prepared form is about the size and dimensions of a size "5" to
size "000" hard gelatin capsule. The cross-sectional shape of the
matrix may be circular or may be oval or other shapes that are able
to be manipulated by the banding system, indexed by means of the
grooves acting as registers and printed. Generally, shapes that are
easily rotated by the printing wheel of the systems described
herein, e.g., circular and oval, will be most preferred.
[0076] The following examples are illustrative of the present
invention. They are not to be construed as limiting the scope of
the invention. Variations and equivalents of these examples will be
apparent to those skilled in the art in light of the present
disclosure, the drawings and the claims herein.
EXAMPLE 1
[0077] A delivery device according to the present invention is
prepared as follows. 580 grams of the analgesic drug, ibuprofen,
250 grams of hydroxypropyl methylcellulose having a number average
molecular weight of 9,200 grams per mole, and 150 grams of
hydroxypropyl methylcellulose having a molecular weight of 242,000
grams per mole, is passed through a screen having a mesh size of 40
wires per inch. The cellulose each have an average hydroxyl content
of 8 weight percent and an average methoxyl content of 22 weight
percent. The resulting sized powders are tumble mixed. Anhydrous
ethyl alcohol is added slowly to the mixed powders with stirring
until a dough consistency is produced. The damp mass is then
extruded through a 20 mesh screen and air dried overnight. The
resulting dried material is re-screened through a 20 mesh screen to
form the final granules. 2 grams of the tabletting lubricant,
magnesium stearate, which has been sized through an 80 mesh screen,
is then tumbled into the granules.
[0078] 690 mg of the resulting granulation is placed in a die
cavity formed with three, uniformly spaced convex ridges, each
having a semi-circular cross-sectional shape and a height of 0.7
mm. The inside dimensions of the die, not including the ridged
areas, are 15 mm by 9 mm. The granulation is horizontally
compressed with deep concave punch tooling using a punch formed
with ridges on its interior surface that correspond to the ridges
in the die to form complementary groove when the compression
operation is completed. Compression takes place at a pressure head
of 2 tons. This forms a longitudinal blank having an overall
length, including the rounded ends, of 15 mm and a concave groove
with a depth of 0.7 mm. The cylindrical body of the blank, from
tablet land to tablet land, spans a distance of 9 mm. Each blank
contains a unit dose of drug of 400 mg. The capsules are fed into a
Tait Capsealer Machine (Tait Design and Machine Co., Manheim, Pa.),
modified as described herein, where the rotating printing wheels
engage the grooves and align the blank for the printing operation.
Three bands are printed onto each capsule. The material forming the
bands is a mixture of 50 wt % ethylcellulose dispersion
(Surelease.RTM., Colorcon, West Point, Pa.) and 50 wt % ethyl
acrylate methylmethacrylate (Eudragit.RTM. NE 30D, RohmPharma,
Weiterstadt, Germany). The bands are applied as an aqueous
dispersion and the excess water is driven off in a current of warm
air. The diameter of the bands is 2 millimeters. The finished
dosage form has a smooth outer surface and delivers ibuprofen over
a prolonged period of time.
[0079] Drug release studies are performed by placing the dosage
forms in a slotted basket. The inside diameter of the basket is 14
mm and the length is 50 mm. The basket is attached to a
reciprocating motor. The basket is then immersed in 50 ml of
simulated intestinal fluid at 37.degree. C., and shaken vertically
in the media with a amplitude of 3.8 cm and a frequency of 99-101
cycles per minute. After 1 hour of shaking, the basket is
transferred to a fresh 50 ml volume of the test media. This
procedure is continued, hour by hour, for nine hours. The systems
then are allowed to release continuously for another 13 hours to
complete a 24 hour test duration. The release receptor solutions
are then analyzed for drug content by ultraviolet spectroscopy. The
release rate as a function of time and cumulative release as a
function of time are computed. The delivery devices of the
invention release active agent over a prolonged period of time.
EXAMPLE 3
[0080] A blank with the ibuprofen matrix formulation described in
Example 1 is formed with one notched groove having sloping side
wall at an angle of 30 degrees with the longitudinal axis of the
tablet and banded with one band. The resulting dosage form has a
substantially smooth outer surface, with the edges and thickness of
the bands being substantially uniform. The dosage form delivers
ibuprofen over a prolonged period.
EXAMPLE 4
[0081] A fast-release drug granulation is prepared as follows; 870
grams of ibuprofen, 100 grams of hydroxypropyl cellulose having a
hydroxypropoxyl content of 11 weight percent, and 10 grams of
hydroxypropyl methyl cellulose having a hydroxypropoxyl content of
8 weight percent and a methoxy content of 22 weight percent and
having a number average molecular weight of 9,200 grams per mole,
are screened through a 40 mesh sieve. The sized powders are mixed
and anhydrous ethanol is added with stirring until a uniform, damp
mass is produced. The mixture is extruded through a 20 mesh sieve.
The elongated granules produced are air dried. The dried granules
are re-screened through a 20 mesh sieve. 20 Grams of stearic acid
which has been passed through an 80 mesh sieve are tumble mixed
into the granules for 3 minutes.
[0082] 690 mg of the granulation of Example 1 is filled into a die
cavity having two semicircular ridges with sides at an angle of 30
degrees with the longitudinal axis of the die and an inside
diameter in an area not including the ridges of 6 mm and
horizontally lightly compressed with deep concave punch tooling.
The upper punch is removed and 230 mg of the fast-release
granulation is placed on the lightly compressed core. A second
upper punch, formed with two ridges that cooperate with the ridges
in the die to create the two grooves in the blank, is placed in the
die cavity and a 2 ton compression force is applied, thereby
forming a two-layered tablet. Two rings are printed onto the dosage
form according to the procedures herein.
[0083] An abrasion resistant, protective coating is applied to the
banded, two-layered tablet as follows. A coating solution is
prepared by dissolving 63 grams of hydroxypropyl methylcellulose
having a hydroxypropoxyl content of 10 weight percent and a methoxy
content of 29 weight percent with a number average molecular weight
of 11,900 grams per mole, and 7 grams of polyethylene glycol having
a molecular weight of 3,350 grams per mole, in 930 grams of water.
The banded dosage form is then placed in a pan coating machine. The
coating solution is sprayed onto the banded tablet in a current of
warmed air until 40 mg of film are deposited on each tablet.
[0084] The resulting two-layer, film coated system releases a
portion of ibuprofen rapidly and a portion of ibuprofen over a
prolonged period.
[0085] The above description has been given for ease of
understanding only. No unnecessary limitations should be understood
therefrom, as modifications will be obvious to those skilled in the
art.
* * * * *