U.S. patent application number 10/476529 was filed with the patent office on 2005-01-27 for composite dosage forms.
Invention is credited to Bunick, Frank J., Lee, Der-Yang, McNally, Gerard P., Sowden, Harry S., Thomas, Martin.
Application Number | 20050019407 10/476529 |
Document ID | / |
Family ID | 27542311 |
Filed Date | 2005-01-27 |
United States Patent
Application |
20050019407 |
Kind Code |
A1 |
Sowden, Harry S. ; et
al. |
January 27, 2005 |
Composite dosage forms
Abstract
A composite dosage form comprises at least one active
ingredient, a first portion comprising a first molded material, and
a second portion comprising a second material which is
compositionally different from the first material. The first and
second portions are joined at an interface, and a surface of the
first portion at the interface resides substantially conformally
upon a surface of the second portion of the interface. Either the
first portion, the second portion, or a combination thereof may
contain at least one active ingredient. The first portion, second
portion or both may also each comprise an insert which may contain
at least one active ingredient. The dosage form may also comprise a
third portion which is located between the first and second
portions.
Inventors: |
Sowden, Harry S.; (Glenside,
PA) ; Bunick, Frank J.; (Randolph, NJ) ;
McNally, Gerard P.; (Berwyn, PA) ; Lee, Der-Yang;
(Flemington, NJ) ; Thomas, Martin; (Lake Worth,
FL) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
27542311 |
Appl. No.: |
10/476529 |
Filed: |
June 10, 2004 |
PCT Filed: |
September 28, 2002 |
PCT NO: |
PCT/US02/31163 |
Related U.S. Patent Documents
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Filing Date |
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10476529 |
Jun 10, 2004 |
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09966939 |
Sep 28, 2001 |
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10476529 |
Jun 10, 2004 |
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09966509 |
Sep 28, 2001 |
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6767200 |
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10476529 |
Jun 10, 2004 |
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09966497 |
Sep 28, 2001 |
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10476529 |
Jun 10, 2004 |
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09967414 |
Sep 28, 2001 |
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6742646 |
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10476529 |
Jun 10, 2004 |
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09966450 |
Sep 28, 2001 |
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Current U.S.
Class: |
424/472 |
Current CPC
Class: |
A61K 9/0004 20130101;
Y10T 428/1352 20150115; B30B 11/08 20130101; A61K 9/2013 20130101;
A61K 9/209 20130101; A61K 9/2095 20130101; A61K 9/284 20130101;
A23G 3/04 20130101; A61K 9/5084 20130101; A61J 3/005 20130101; A61K
9/2873 20130101; A61K 9/2054 20130101; A61K 9/282 20130101; A23G
1/54 20130101; A61P 11/00 20180101; A61K 9/2031 20130101; A61J 3/06
20130101; A61J 3/10 20130101; A61K 9/286 20130101; A61K 9/2886
20130101; A61K 9/2893 20130101; A61K 9/2826 20130101; A23L 29/30
20160801; A61K 9/2081 20130101; A61K 9/2027 20130101; A23G 3/0029
20130101; A61P 43/00 20180101; A23G 3/54 20130101; A61K 9/0056
20130101; B30B 11/34 20130101; A23G 3/368 20130101; B30B 15/302
20130101; A61K 9/2018 20130101; A61K 9/2072 20130101; A61K 9/2068
20130101 |
Class at
Publication: |
424/472 |
International
Class: |
A61K 009/24 |
Claims
1. A dosage form comprising at least one active ingredient, a first
portion comprising a first molded material, and a second portion
comprising a second material which is compositionally different
from the first material, wherein the first and second portions are
joined at an interface, and a surface of the first portion at the
interface resides substantially conformally upon a surface of the
second portion at the interface.
2. The dosage form of claim 1, wherein the first portion comprises
a thermoplastic material.
3. The dosage form of claim 1, wherein the first molded material is
substantially free of pores having a diameter of 0.5 to 5.0
microns.
4. The dosage form of claim 1, wherein the first portion comprises
a foam.
5. The dosage form of claim 1, wherein the first portion comprises
an aerated material.
6. The dosage form of claim 1, in which the active ingredient is
coated with a release-modifying coating.
7. The dosage form of claim 1, in which the first and second
portions are in substantial contact at the interface.
8. The dosage form of claim 1, in which the interface is in the
form of an abutment.
9. The dosage form of claim 1, in which the first and second
portions overlap at the interface.
10. The dosage form of claim 1, in which the first and second
portions interlock at the interface.
11. The dosage form of claim 1, in which the first and second
portions dissociate upon immersion in aqueous media.
12. The dosage form of claim 1, further comprising a third portion,
which is located between the first and second portions.
13. The dosage form of claim 12, in which the third portion
comprises a chemical reaction product of the first and second
materials.
14. The dosage form of claim 12, in which the third portion is
impermeable to one or more active ingredients contained in the
dosage form.
15. The dosage form of claim 12, in which the third portion is
impermeable to water.
16. The dosage form of claim 12, in which the third portion acts as
a barrier to the passage therethrough of one or more active
ingredients contained in the first or second portions.
17. The dosage form of claim 12, in which the third portion
functions to control the passage of one or more active ingredients
contained in the first or second portions.
18. The dosage form of claim 12, in which the third portion
comprises openings which allow the passage of one or more active
ingredients therethrough.
19. The dosage form of claim 12, in which the third portion
comprises a microelectronic device.
20. The dosage form of claim 1, in which the first and second
portions have different colors.
21. The dosage form of claim 1, in which the first and second
portions have different opacities.
22. The dosage form of claim 1, in which the first and second
portions have different solubilities in acidic, alkaline or neutral
aqueous media.
23. The dosage form of claim 1, in which the first and second
portions have different dissolution rates in acidic, alkaline or
neutral aqueous media.
24. The dosage form of claim 1, in which the first and second
portions have different disintegration times in acidic, alkaline or
neutral aqueous media.
25. The dosage form of claim 1, in which the first and second
portions have different hydrophilicities.
26. The dosage form of claim 1, in which the first and second
portions have different topographies.
27. The dosage form of claim 1, in which the first and second
portions have different elasticities.
28. The dosage form of claim 1, in which the first and second
portions have different plasticities.
29. The dosage form of claim 1, in which the first and second
portions have different tensile strengths.
30. The dosage form of claim 1, in which the first and second
portions have different crystallinities.
31. The dosage form of claim 1, in which the first and second
portions each comprise at least one active ingredient, and release
active ingredient at different rates.
32. The dosage form of claim 1, wherein the first portion is
obtained by injection molding.
33. The dosage form of claim 1, wherein the second portion is a
substrate, and the first portion is formed directly upon the first
portion.
34. The dosage form of claim 1, in which the first portion
comprises at least one active ingredient.
35. The dosage form of claim 1, in which the second portion
comprises at least one active ingredient.
36. The dosage form of claim 1, in which both the first and the
second portions comprise at least one active ingredient which may
be the same or different.
37. The dosage form of claim 1, in which the first portion further
comprises an insert.
38. The dosage form of claim 1, in which the second portion further
comprises an insert.
39. The dosage form of claim 37, in which the insert is molded.
40. The dosage form of claim 1, in which the first portion is
contained within the second portion.
41. The dosage form of claim 1, in which at least one active
ingredient is capable of dissolution, and dissolution of the active
ingredient meets USP specifications for immediate release tablets
containing the active ingredient.
42. The dosage form of claim 1, in which the second material is a
compressed material.
43. The dosage form of claim 1, in which either the first portion,
the second portion or both comprises a microelectronic device.
44. The dosage form of claim 1, in which a shell resides upon the
outer surfaces of the first and second portions.
45. The dosage form of claim 1, wherein the surface of the first
portion at the interface has indentations and protrusions
corresponding substantially inversely to indentations and
protrusions on the surface of the second portion at the
interface.
46. The dosage form of claim 45, wherein the indentations and
protrusions have a length, width, height or depth greater than 10
microns.
47. The dosage form of claim 1, wherein the area of the interface
surfaces is at least 50% of the area of a major face of either the
first or second portion.
48. The dosage form of claim 1, wherein an entire face of the first
portion is in substantial contact with the second portion.
49. The dosage from of claim 1, wherein an entire face of the
second portion is in substantial contact with the first
portion.
50. The dosage form of claim 1 wherein one face or side of the
second portion comprises a cavity, and the first portion is in
contact with the entire surface of the cavity.
51. The dosage form of claim 1, wherein at least one exterior
surface of the first portion is flush with at least one exterior
surface of the second portion.
52. The dosage form of claim 38, in which the insert is molded.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to composite dosage forms such as
pharmaceutical compositions. More particularly, this invention
relates to composite dosage forms comprising at least one active
ingredient and having a first portion comprising a first molded
material and a second portion comprising a second material, in
which the second material is compositionally different than the
first material, surfaces of the first and second portions are
joined at an interface, and the first portion surface at the
interface resides substantially conformally upon the second portion
surface at the interface.
[0003] 2. Background Information
[0004] Dosage forms having two or more distinct portions are useful
in the pharmaceutical arts for overcoming a number of commonly
encountered challenges, including the separation of incompatible
active ingredients, achieving acceptable content uniformity of a
low-dose/high potency active ingredient, delivering one or more
active ingredients in a pulsatile manner, and providing unique
aesthetic characteristics for dosage form identification. Known
methods for achieving a multi-portion pharmaceutical dosage form
include particle coating, multi-layer tablets, compression-coating,
and spray coating techniques. It is also known for example in the
household products industry to assemble solid forms from two or
more different parts for the purpose of separating active
ingredients, or delivering different active ingredients at
different times.
[0005] Dosage forms comprising coated particles are described for
example in U.S. Pat. No. 5,593,696, which describes oral dosage
forms for treating of gastric disorders. The dosage forms contain,
as active ingredients, famotidine and sucralfate. In the dosage
form, the famotidine is present in the composition in particulate
(granulate) form, and the particulate famotidine is provided with a
protective barrier layer which prevents interaction between the
famotidine and the sucralfate in the composition. The barrier layer
is preferably a polymeric coat which dissolves partially in vivo in
the stomach environs to release the coated famotidine. U.S. Pat.
No. 5,980,944 describes a solid oral dosage form for the treatment
of gastrointestinal disorders comprising a therapeutically
effective amount of a pharmaceutical suitable for the treatment of
gastric disorders selected from the group consisting of granules of
diphenoxylate, loperamide, loperamide-N-oxide, pharmaceutically
acceptable salts thereof and combinations thereof, and a
therapeutically effective amount of simethicone wherein the
pharmaceutical and simethicone are separated by a barrier coat on
the granules which is substantially impermeable to simethicone.
[0006] Multi-layer tablets are described, for example, in U.S. Pat.
No. 5,200,193, which describes multi-layered pharmaceutical active
tablets comprising an immediate release layer and a homogeneous
compressed sustained release layer comprising an erosion promoter,
which upon administration results in a long-lasting, slow and
relatively regular incremental release of the pharmaceutical active
ingredient. U.S. Pat. No. 6,372,252 describes a pharmaceutical
sustained release formulation capable of providing therapeutically
effective bioavailability of guaifenesin for at least twelve hours
after dosing in a human subject. The modified release guaifenesin
bi-layer tablet disclosed has a first portion comprising an
immediate release formulation of guaifenesin and a second portion
comprising a sustained release formulation of guaifenesin. U.S.
Pat. No. 4,999,226 discloses a multi-layered tablet containing an
ibuprofen layer, a piperidino-alkanol antihistamine layer, and a
layer or layers containing conventional pharmaceutical excipients
which is interspersed between the ibuprofen and piperidino-alkanol
layer and serves to physically separate them. This multi-layered
tablet solves the problems associated with the physical and
chemical incompatibilities between ibuprofen and the
piperidinoalkanol antihistamines. U.S. Pat. No. 4,198,390 describes
a tablet containing at least two separate and discrete volume
portions, one of which contains simethicone and the other of which
contains antacid. A barrier separates the two volume portions to
maintain the simethicone out of contact with the antacid and to
prevent migration of the simethicone from its volume portion of the
tablet into the volume portion containing the antacid, and vice
versa. U.S. Pat. No. 5,133,892 describes a multilayer detergent
tablet containing an outer layer, a barrier layer and an inner
layer. The tablet sequentially releases ingredients contained in
the outer layer and ingredients contained in the inner layer. The
time interval between the release of the outer layer ingredients
and the release of the inner layer ingredients is controlled by the
particular choice of an ingredient for the barrier layer and the
relative thicknesses of the inner layer, the barrier layer and the
outer layer. The tablet is able to separate in time the dissolution
of incompatible ingredients such as an enzyme and a chlorine
bleach. The tablet also provides sequential release of a
dishwashing composition and a rinse aid composition such that
cleaning is accomplished prior to the release of the rinse aid.
[0007] Compression-coated tablets are useful for separation of
incompatible active ingredients, and for pulsatile release of one
or more active ingredients. Compressed coatings may have shapes
which are substantially independent of the shape of the core, as
disclosed for example in WO 00/18447. Commercially available
compression coating machines are available for example from Korsch
America Inc., a subsidiary of Korsch AG, and described in WO
89/11968. Modified release dosage forms prepared via compression
are exemplified in U.S. Pat. Nos. 5,738,874 and 6,294,200, and WO
99/51209. It is possible, via compression-coating, to produce a
2-portion shell, which may function as a barrier, or release
delaying coating; however compression-coated systems are limited by
the shell thickness and shell composition as well as processing
costs. Gunsel et al., "Compression-Coated and Layer Tablets" in
Pharmaceutical Dosage Forms--Tablets, edited by H. A. Lieberman, L.
Lachman, J. B. Schwartz (2nd ed., rev. and expanded Marcel Dekker,
Inc.) pp. 247-284, for example, discloses the thickness of
compression coated shells is typically between 800 and 1200
microns. Additionally these authors note that "the advent of film
coating dissipated much of the advantage of dry coating since
larger quantities of tablets can be coated in a short time with
film-formers dissolved in organic or aqueous solvents." Typically,
compressed coatings must contain a substantial amount of a
compressible material. The compressed shell of WO 00/18447, for
example, employs microcrystalline cellulose at a level of about
30%.
[0008] One method for addressing the challenge of low-dose/high
potency actives is described for example in U.S. Pat. No. 4,322,449
and U.S. RE 31764, which disclose a method for the preparation of
pharmaceuticals which comprises using a piezoelectric dosing system
to dot liquid, dissolved or suspended active substance onto a
pharmaceutical carrier. The disclosed method enables precise dosing
of active pharmaceutical ingredients onto pharmaceutical carriers.
The dotting is effected by, for example, use of tubular or
plate-shaped piezoelectric dosing systems. However, the liquid,
dissolved or suspended active substance can also be divided into
discrete droplets of specific volume after application of a high
pressure during passage through a narrow nozzle, whereby the
individual droplets are successively charged electrically and are
intermittently deflected electrostatically towards the
pharmaceutical carriers.
[0009] The incorporation of molded portions into delivery systems
has been used in the household products industry to achieve an
additional degree of versatility. Assembled forms comprising a
mixture of compressed and molded portions are known for example for
delivery of detergents. WO 01/49815 describes a composition for use
in a dishwasher characterized by a base composition in the form of
a tablet which becomes active substantially during the main wash
cycle, and at least one separate zone in or on the tablet is
provided with a substance that becomes active substantially during
the rinse cycle of the dishwasher. One example of such assembled
forms comprises a compressed tablet portion having a hemispherical
indentation in a major face, and a molded spherical portion fit
into and adhered to the indentation in the compressed portion. One
limitation of such assemblies is the propensity for the two
portions to become detached due to inadequate adherance and minimal
surface area of contact between them. In such assemblies, the
molded portion may be smaller than the indentation in the
compressed portion, e.g. the diameter of the molded portion is at
least about 20 microns less that the diameter of the opening in the
compressed portion. Alternatively, similar forms may be assembled
by press-fitting. In these forms the dimensions of the molded
portion and the opening in the compressed portion may be similar.
Such assemblies are additionally limited in the types of geometries
that are possible at the interface. In press-fit assemblies, the
width of the molded portion at the deepest part of the interface
may not be substantially larger than the width of the opening
through which it must be fit. In other words the draft angle
between the outer and inner surfaces of the compressed portion may
not be negative. Moreover, the interface or area of contact between
the two portions may not form an interlock.
[0010] Another significant opportunity in designing pharmaceutical
dosage forms is that of product identification and differentiation.
It is useful, both from a consumer safety perspective, and a
commercial perspective, to have a dosage form with a unique
appearance that is readily recognizable and identifiable.
[0011] Current techniques for providing unique dosage form
identification include the use of intagliations. Intagliations are
impressed marks typically achieved by engraving or impressing of a
graphical representation, for example a figure, mark, character,
symbol such as a letter, a name, a logo, a pictoral representation,
and the like, or any combination thereof, in a tablet or other
solid dosage form, preferably by a punching procedure. U.S. Pat.
No. 5,827,535, for example, describes soft gelatin capsules having
an external surface having defined thereon an impressed graphical
representation. U.S. Pat. No. 5,405,642 discloses a method of
highlighting intagliations in white or colored coated tablets by
spraying onto said tablets a suspension comprising a filling
material having a different color, a waxy material and a solvent,
and removing the solvent and the excess of filling material and
waxy material. The suspension of U.S. Pat. No. 5,405,642 comprises
a waxy material and a filling material in a critical weight ratio
from about 1:3 to about 1:12. Too little waxy material will lead to
insufficient bonding of the filling material; too much waxy
material the filling material will bond too strongly to the tablet
surface and consequently will be difficult to remove afterwards.
Suitable solvents for the suspension of U.S. Pat. No. 5,405,642 are
those solvents wherein the filling material and, if present, the
dye, do not dissolve. For example, non-dyed starches and celluloses
may be suspended in alcohols, e.g. ethanol, isopropanol and the
like, halogenated hydrocarbons, e.g. dichloromethane,
trichloromethane and the like. EP 060,023 discloses a method of
emphasizing intagliations in colored (i.e. not white) solid
articles, in particular tablets, by coating the tablet surface and
filling up the intagliations with a coating film comprising an
optically anisotropic substance. An optical contrast between the
tablet surface and the intagliations is obtained, presumably due to
the different orientation of the optically anisotropic substance on
the tablet surface and in the intagliations. The technique is
limited to colored articles and only allows the use of optically
anisotropic filling materials. The optical effect merely being
based on a different contrast is not particularly clear.
[0012] EP 088,556 relates to a method of highlighting intagliations
in white or colored tablets by contacting said tablets with a dry,
powdery material having a different color than the tablet surface
and then removing the excess powdery material not deposited in the
intagliations. The powdery material is thought to adhere better to
the intagliations of coated tablets than to those of uncoated
tablets. Adherence can further be increased by using a mixture of a
wax and a powdery material as the deposition material and heating
the filled tablets to 40.degree. C.-90.degree. C. to melt the wax.
Finally, an outer coating may be applied to the filled tablets.
However, the method disclosed in EP 088,556 has several problems.
First, it has been found that the adhesion of the powdery material
to the intagliations is not satisfactory as the material shows a
tendency to loosen and fall out. This problem arises particularly
when an outer coating film is applied to the filled tablet and the
loosened material becomes fixed in the outer coating film, thus
yielding speckled tablets. Addition of a wax to the powdery
material to improve adhesion, on the other hand, adversely affects
the distribution of the powdery material in that more of it sticks
to the surface of the tablet and is difficult to remove. Several
other drawbacks are associated with the use of a wax in the dry
powdery material. In particular the necessity to heat the tablets
filled with a wax and a powdery material to melt the wax poses a
barely acceptable risk since many medicines are thermolabile and
might deteriorate significantly in the process. Further, it is
difficult to evenly dye a dry mixture of a wax and a powdery
material, which in turn puts a limitation on the effectively
possible color combinations.
[0013] U.S. Pat. No. 4,139,589 describes a process for the
manufacture of an inlaid tablet, comprising the steps of
incorporating into a plastic chewing gum mass a sustained-release
active ingredient; incorporating into a non-plastic tablet mass a
substantially immediate-release pharmaceutically active ingredient;
and respectively converting the chewing gum mass and the tablet
mass into the core and the outer layer of the inlaid tablet. A
preferred embodiment includes converting the tablet mass into a
recessed preformed element, converting the chewing gum mass into
the core, inserting the core into the recess of the preformed
element, introducing the preformed element and the core into a
tablet mold, and subjecting the preformed element and the core in
the mold to pressure.
[0014] All of the methods described above for producing a dosage
form having one or more separate portions are relatively costly,
complex, and time-intensive. Additionally, known methods for
producing filled-in intagliations are limited in terms of suitable
materials and the obtainable surface configurations and appearance
of the resultant dosage form. Besides the above-mentioned
limitations on the fill material itself, the tablet subcoating must
be non-adhesive enough for the fill-in material to rub off upon
tumbling in a hot coating pan. These methods cannot produce
filled-in intagliations having the fill material raised above the
tablet surface, or even perfectly flush with the tablet surface.
The prior art product can only have a fill-in material surface that
is slightly depressed, abraided, or concave with respect to the
tablet surface.
[0015] Another significant challenge in the pharmaceutical industry
is the opportunity to minimize manufacturing and packaging costs
through standardization. Many drugs are available in several
different strength tablets for convenience of dosing different
patients with varying needs. Typically, higher strength tablets
have greater weight and larger size than tablets having lower
amounts of active ingredient. Handling and packaging costs could be
reduced by having a dosage form design with the versatility to
accommodate multiple different dosage amounts of medication in the
same size tablet, yet be readily identifiable to patients and
healthcare professionals in terms of identity and strength.
[0016] All of the prior art methods for forming a shell on a core
share the common limitation of having the shape of the shell depend
upon and generally conform to the shape of the core. Other
limitations shared by conventional encapsulation and enrobing
processes include high cost and complexity, limitations on the
thickness of the coating or shell, and the creation of raised seams
between capsule halves and/or coatings.
[0017] In addition, the separation of incompatible ingredients in
pharmaceutical dosage forms presents a significant challenge to the
formulator. This challenge has primarily been addressed in the art
through the use of relatively costly and time-intensive methods of
coated particles, multiple layer compressed tablets, or compression
coating.
[0018] Another significant challenge in the formulation of
pharmaceutical dosage forms is that of providing multiple release
profiles for multiple active ingredients. This challenge has
primarily been addressed in the art through the use of coated
particles, or sprayed or compressed tablet coatings, all of which
add cost and complexity to the manufacturing process.
[0019] The incorporation of molded portions into delivery systems,
has been used in the household products industry to achieve an
additional degree of versatility. Assembled forms comprising a
mixture of compressed and molded portions are known, for example,
for delivery of detergents. WO 01/49815 describes a composition for
use in a dishwasher characterized by a base composition in the form
of a tablet which becomes active substantially during the main wash
cycle, and at least one separate zone in or on the tablet is
provided with a substance that becomes active substantially during
the rinse cycle of the dishwasher. One example of such assembled
forms comprises a compressed tablet portion having a hemispherical
indentation in a major face, and a molded spherical portion fit
into and adhered to the indentation in the compressed portion.
However, a limitation of such assemblies is the propensity for the
two portions to become detached due to inadequate adherance and
minimal surface area of contact therebetween. In such assemblies,
the molded portion may be smaller than the indentation in the
compressed portion, e.g. the diameter of the molded portion is at
least about 20 microns less that the diameter of the opening in the
compressed portion. Alternatively, similar forms may be assembled
by press-fitting. In these forms the dimensions of the molded
portion and the opening in the compressed portion may be similar.
Such assemblies are additionally limited in the types of geometries
that are possible at the interface. In press-fit assemblies, the
width of the molded portion at the deepest part of the interface
may not be substantially larger than the width of the opening
through which it must be fit. In other words, the "draft angle"
between the outer and inner surfaces of the compressed portion may
not be negative. Moreover, the interface or area of contact between
the two portions may not form an interlock.
[0020] Accordingly, it is one object of this invention to provide a
dosage form comprising at least one active ingredient and a first
portion comprising a first molded material and a second portion
comprising a second material, in which the second material is
compositionally different than the first material, the first and
second material are joined at an interface, and a surface of the
first portion at the interface resides substantially conformally
upon a surface of the second portion of the interface.
[0021] It is another object of this invention to provide a dosage
form comprising at least one active ingredient, a first portion
comprising a first molded material, a second portion comprising a
second material which is compositionally different from the first
material, and a third portion which is located between the first
and second portions.
[0022] Dosage forms of the present invention advantageously have
enhanced versatility for a number of applications, including dosage
forms to deliver pharmaceuticals, nutritionals and/or confections,
which may offer benefits of improved swallowability for an
irregularly shaped substrate, or unique and pleasant aesthetic
qualities that are valuable in the marketplace.
[0023] The dosage form of the present invention also advantageously
provides a cost-effective means for ensuring acceptable content
uniformity, and improved safety of handling for low-dose/high
potency active ingredients. Low dose active ingredients can be
homogeneously dispersed in the molded portion when it is in a
flowable state. This eliminates problems associated with powder
segregation in blends for tableting, and minimizes exposure of
workers to potential inhalation of dust containing the high potency
active ingredient.
[0024] Other objects, features and advantages of this invention
will be apparent to those skilled in the art from the detailed
description of the invention provided herein.
SUMMARY OF THE INVENTION
[0025] The dosage form of this invention comprises at least one
active ingredient, a first portion comprising a first molded
material and a second portion comprising a second material which is
compositionally different than the first material. For example, the
second material may be a compressed material such as a compressed
powder. Surfaces of the first and second portions are joined at an
interface, such that the surface of the first portion resides
substantially conformally upon the surface of the second portion at
the interface.
[0026] In one embodiment, the first portion comprises a
thermoplastic material.
[0027] In another embodiment, the first molded material is
substantially free of pores having a diameter of 0.5 to 5.0
microns.
[0028] In another embodiment, the first portion comprises a
foam.
[0029] In another embodiment, the first portion comprises an
aerated material.
[0030] In another embodiment, the active ingredient is coated with
a release-modifying coating.
[0031] In another embodiment, the first and second portions are in
substantial contact at the interface.
[0032] In another embodiment, the interface is in the form of an
abutment.
[0033] In another embodiment, the first and second portions overlap
at the interface.
[0034] In another embodiment, the first and second portions
interlock at the interface.
[0035] In another embodiment, the first and second portions
dissociate upon immersion in aqueous media.
[0036] In another embodiment, the dosage form further comprises a
third portion, which is located between the first and second
portions.
[0037] In another embodiment, the third portion comprises a
chemical reaction product of the first and second materials.
[0038] In another embodiment, the third portion is impermeable to
one or more active ingredients contained in the dosage form.
[0039] In another embodiment, the third portion is impermeable to
water.
[0040] In another embodiment, the third portion acts as a barrier
to the passage therethrough of one or more active ingredients
contained in the first or second portions.
[0041] In another embodiment, the third portion functions to
control the passage of one or more active ingredients contained in
the first or second portions.
[0042] In another embodiment, the third portion comprises openings
which allow the passage of one or more active ingredients
therethrough.
[0043] In another embodiment, the third portion comprises a
microelectronic device.
[0044] In another embodiment, the first and second portions have
different colors.
[0045] In another embodiment, the first and second portions have
different opacities.
[0046] In another embodiment, the first and second portions have
different solubilities in acidic, alkaline, or neutral aqueous
media.
[0047] In another embodiment, the first and second portions have
different dissolution rates in acidic, alkaline, or neutral aqueous
media.
[0048] In another embodiment, the first and second portions have
different disintegration times in acidic, alkaline, or neutral
aqueous media.
[0049] In another embodiment, the first and second portions have
different hydrophilicities.
[0050] In another embodiment, the first and second portions have
different topographies.
[0051] In another embodiment, the first and second portions have
different elasticities.
[0052] In another embodiment, the first and second portions have
different plasticities.
[0053] In another embodiment, the first and second portions have
different tensile strengths.
[0054] In another embodiment, the first and second portions have
different crystallinities.
[0055] In another embodiment, the first and second portions each
comprise at least one active ingredient, and release active
ingredient at different rates.
[0056] In another embodiment, the first portion is obtained by
injection molding.
[0057] In another embodiment, the second portion is a substrate,
and the first portion is formed directly upon the first
portion.
[0058] In another embodiment, the first portion comprises at least
one active ingredient.
[0059] In another embodiment, the second portion comprises at least
one active ingredient.
[0060] In another embodiment, the first and the second portion each
comprise at least one active ingredient which may be the same or
different.
[0061] In another embodiment, the first portion further comprises
an insert.
[0062] In another embodiment, the second portion further comprises
an insert.
[0063] In another embodiment, the insert is molded.
[0064] In another embodiment, the first portion is contained within
the second portion.
[0065] In another embodiment, at least one active ingredient is
capable of dissolution, and dissolution of the active ingredient
meets USP specifications for immediate release tablets containing
the active ingredient.
[0066] In another embodiment, the second material is a compressed
material.
[0067] In another embodiment, either the first portion, the second
portion or both comprises a microelectronic device.
[0068] In another embodiment, a shell resides upon the outer
surfaces of the first and second portions.
[0069] In another embodiment, the surface of the first portion at
the interface has indentations and protrusions corresponding
substantially inversely to indentations and protrusions on the
surface of the second portion at the interface.
[0070] In another embodiment, wherein the indentations and
protrusions have a length, width, height or depth greater than 10
microns.
[0071] In another embodiment, the area of the interface surfaces is
at least 50% of the area of a major face of either the first or
second portion.
[0072] In another embodiment, an entire face of the first portion
is in substantial contact with the second portion.
[0073] In another embodiment, an entire face of the second portion
is in substantial contact with the first portion.
[0074] In another embodiment, a side or face of the second portion
comprises a cavity, and the first portion is in contact with the
entire surface of the cavity.
[0075] In another embodiment, at least one exterior surface of the
first portion is flush with at least one exterior surface of the
second portion.
BRIEF DESCRIPTION OF THE DRAWINGS
[0076] FIGS. 1A and 1B are top and side views of an embodiment of
this invention.
[0077] FIGS. 2A and 2B are top and side views of another embodiment
of this invention.
[0078] FIGS. 3A and 3B are top and side views of another embodiment
of this invention.
[0079] FIGS. 4A and 4B are top and side views of another embodiment
of this invention.
[0080] FIGS. 5A and 5B are top and side views of another embodiment
of this invention.
[0081] FIGS. 6A and 6B are top and side views of another embodiment
of this invention.
[0082] FIGS. 7A-7C are top, side and exploded views of another
embodiment of this invention.
[0083] FIGS. 8A-8C side views of other embodiments of this
invention.
[0084] FIGS. 9A and 9B are top and side views of another embodiment
of this invention.
[0085] FIG. 10 is a side view of another embodiment of this
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0086] As used herein, the term "dosage form" applies to any solid
object, semi-solid, or liquid composition, designed to contain a
specific pre-determined amount (i.e. dose) of a certain ingredient,
for example an active ingredient as defined below. Suitable dosage
forms may be pharmaceutical drug delivery systems, including those
for oral administration, buccal administration, rectal
administration, topical, transdermal, or mucosal delivery, or
subcutaneous implants, or other implanted drug delivery systems; or
compositions for delivering minerals, vitamins and other
nutraceuticals, oral care agents, flavorants, and the like.
Preferably the dosage forms of the present invention are considered
to be solid, however they may contain liquid or semi-solid
components. In a particularly preferred embodiment, the dosage form
is an orally administered system for delivering a pharmaceutical
active ingredient to the gastro-intestinal tract of a human. In
another preferred embodiment, the dosage form is an orally
administered "placebo" system containing pharmaceutically inactive
ingredients, and the dosage form is designed to have the same
appearance as a particular pharmaceutically active dosage form,
such as may be used for control purposes in clinical studies to
test, for example, the safety and efficacy of a particular
pharmaceutically active ingredient.
[0087] Suitable active ingredients for use in the dosage form of
this invention include for example pharmaceuticals, minerals,
vitamins and other nutraceuticals, oral care agents, flavorants and
mixtures thereof. Suitable pharmaceuticals include analgesics,
anti-inflammatory agents, antiarthritics, anesthetics,
antihistamines, antitussives, antibiotics, anti-infective agents,
antivirals, anticoagulants, antidepressants, antidiabetic agents,
antiemetics, anti flatulents, antifungal s, antispasmodics,
appetite suppressants, bronchodilators, cardiovascular agents,
central nervous system agents, central nervous system stimulants,
decongestants, diuretics, expectorants, gastrointestinal agents,
migraine preparations, motion sickness products, mucolytics, muscle
relaxants, osteoporosis preparations, polydimethylsiloxanes,
respiratory agents, sleep-aids, urinary tract agents and mixtures
thereof.
[0088] Suitable oral care agents include breath fresheners, tooth
whiteners, antimicrobial agents, tooth mineralizers, tooth decay
inhibitors, topical anesthetics, mucoprotectants, and the like.
[0089] Suitable flavorants include menthol, peppermint, mint
flavors, fruit flavors, chocolate, vanilla, bubblegum flavors,
coffee flavors, liqueur flavors and combinations and the like.
[0090] Examples of suitable gastrointestinal agents include
antacids such as calcium carbonate, magnesium hydroxide, magnesium
oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate,
dihydroxyaluminum sodium carbonate; stimulant laxatives, such as
bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe,
castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures
thereof; H2 receptor antagonists, such as famotadine, ranitidine,
cimetadine, nizatidine; proton pump inhibitors such as omeprazole
or lansoprazole; gastrointestinal cytoprotectives, such as
sucraflate and misoprostol; gastrointestinal prokinetics, such as
prucalopride, antibiotics for H. pylori, such as clarithromycin,
amoxicillin, tetracycline, and metronidazole; antidiarrheals, such
as diphenoxylate and loperamide; glycopyrrolate; antiemetics, such
as ondansetron, analgesics, such as mesalamine.
[0091] In one embodiment of the invention, the active agent may be
selected from bisacodyl, famotadine, ranitidine, cimetidine,
prucalopride, diphenoxylate, loperamide, lactase, mesalamine,
bismuth, antacids, and pharmaceutically acceptable salts, esters,
isomers, and mixtures thereof.
[0092] In another embodiment, the active agent is selected from
analgesics, anti-inflammatories, and antipyretics, e.g.
non-steroidal anti-inflammatory drugs (NSAIDs), including propionic
acid derivatives, e.g. ibuprofen, naproxen, ketoprofen and the
like; acetic acid derivatives, e.g. indomethacin, diclofenac,
sulindac, tolmetin, and the like; fenamic acid derivatives, e.g.
mefanamic acid, meclofenamic acid, flufenamic acid, and the like;
biphenylcarbodylic acid derivatives, e.g. diflunisal, flufenisal,
and the like; and oxicams, e.g. piroxicam, sudoxicam, isoxicam,
meloxicam, and the like. In a particularly preferred embodiment,
the active agent is selected from propionic acid derivative NSAID,
e.g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen,
indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin,
pranoprofen, suprofen, and pharmaceutically acceptable salts,
derivatives, and combinations thereof.
[0093] In another embodiment of the invention, the active agent may
be selected from acetaminophen, acetyl salicylic acid, ibuprofen,
naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine,
meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable
salts, esters, isomers, and mixtures thereof.
[0094] In another embodiment of the invention, the active agent may
be selected from pseudoephedrine, phenylpropanolamine,
chlorpheniramine, dextromethorphan, diphenhydramine, astemizole,
terfenadine, fexofenadine, loratadine, desloratidine, doxilamine,
norastemizole, cetirizine, mixtures thereof and pharmaceutically
acceptable salts, esters, isomers, and mixtures thereof.
[0095] Examples of suitable polydimethylsiloxanes, which include,
but are not limited to dimethicone and simethicone, are those
disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260,
the contents of each is expressly incorporated herein by reference.
As used herein, the term "simethicone" refers to the broader class
of polydimethylsiloxanes, including but not limited to simethicone
and dimethicone.
[0096] The active ingredient or ingredients are present in the
dosage form in a therapeutically effective amount, which is an
amount that produces the desired therapeutic response upon oral
administration and can be readily determined by one skilled in the
art. In determining such amounts, the particular active ingredient
being administered, the bioavailability characteristics of the
active ingredient, the dose regime, the age and weight of the
patient, and other factors must be considered, as known in the art.
In one particular embodiment, the first or second portion comprises
at least about 85 weight percent of the active ingredient.
[0097] If the active ingredient has an objectionable taste, and the
dosage form is intended to be chewed or disintegrated in the mouth
prior to swallowing, the active ingredient may be coated with a
taste masking coating, as known in the art. Examples of suitable
taste masking coatings are described in U.S. Pat. No. 4,851,226,
U.S. Pat. No. 5,075,114, and U.S. Pat. No. 5,489,436. Commercially
available taste masked active ingredients may also be employed. For
example, acetaminophen particles which are encapsulated with
ethylcellulose or other polymers by a coaccervation process may be
used in the present invention. Coaccervation-encapsulated
acetaminophen may be purchased commercially from Eurand America,
Inc. (Vandalia, Ohio) or from Circa Inc., (Dayton, Ohio).
[0098] In embodiments where an active ingredient is contained
within the first or second portion of the dosage form, at least a
portion of the active ingredient may be optionally coated with a
release-modifying coating, as known in the art. This advantageously
provides an additional tool for modifying the release profile of
the dosage form. Examples of suitable release modifying coatings
are described, for example, U.S. Pat. Nos. 4,173,626; 4,863,742;
4,980,170; 4,984,240; 5,286,497; 5,912,013; 6,270,805; and
6,322,819. Commercially available modified release coated active
particles may also be employed. Accordingly, all or a portion of
one or more active ingredients may be coated with a
release-modifying material.
[0099] The active ingredient or ingredients may be present in the
dosage form in any form. For example, the active ingredient may be
dispersed at the molecular level, e.g. melted or dissolved, within
the dosage form, or may be in the form of particles, which in turn
may be coated or uncoated. If the active ingredient is in form of
particles, the particles (whether coated or uncoated) typically
have an average particle size of about 1-2000 microns. In one
preferred embodiment, such particles are crystals having an average
particle size of about 1-300 microns. In another preferred
embodiment, the particles are granules or pellets having an average
particle size of about 50-2000 microns, preferably about 50-1000
microns, most preferably about 100-800 microns.
[0100] The first portion of the dosage form is prepared by molding.
The first portion may have any shape that can be molded, and has an
area of its surface that is in contact with the second portion of
the dosage form. Preferably, a substantial proportion of the
surface area of one entire face of the first molded portion has a
shape which is defined by the shape of the second portion.
[0101] The second portion of the dosage form may be prepared by any
suitable method, for example it may be molded or compressed. In one
embodiment, the second portion has one or more major faces. If the
second portion is molded, it may have any shape that can be
molded.
[0102] Molded shapes which may be used for the first portion or
second portion (if molded) include a truncated cone; a polyhedron,
such as a cube, pyramid, prism, or the like; or a shape having the
geometry of a space figure with some non-flat faces, such as a
cone, cylinder, sphere, torus, or the like.
[0103] If the second portion is compressed, it may have any shape
that can be compressed. Suitable shapes for compressed dosage forms
include tablet shapes formed from compression tooling shapes
described by "The Elizabeth Companies Tablet Design Training
Manual" (Elizabeth Carbide Die Co., Inc., p.7 (McKeesport, Pa.)
(incorporated herein by reference) as follows (the tablet shape
corresponds inversely to the shape of the compression tooling):
[0104] 1. Shallow Concave.
[0105] 2. Standard Concave.
[0106] 3. Deep Concave.
[0107] 4. Extra Deep Concave.
[0108] 5. Modified Ball Concave.
[0109] 6. Standard Concave Bisect.
[0110] 7. Standard Concave Double Bisect.
[0111] 8. Standard Concave European Bisect.
[0112] 9. Standard Concave Partial Bisect.
[0113] 10. Double Radius.
[0114] 11. Bevel & Concave.
[0115] 12. Flat Plain.
[0116] 13. Flat-Faced-Beveled Edge (F.F.B.E.).
[0117] 14. F.F.B.E. Bisect.
[0118] 15. F.F.B.E. Double Bisect.
[0119] 16. Ring.
[0120] 17. Dimple.
[0121] 18. Ellipse.
[0122] 19. Oval.
[0123] 20. Capsule.
[0124] 21. Rectangle.
[0125] 22. Square.
[0126] 23. Triangle.
[0127] 24. Hexagon.
[0128] 25. Pentagon.
[0129] 26. Octagon.
[0130] 27. Diamond.
[0131] 28. Arrowhead.
[0132] 29. Bullet.
[0133] 30. Barrel.
[0134] 31. Half Moon.
[0135] 32. Shield.
[0136] 33. Heart.
[0137] 34. Almond.
[0138] 35. House/Home Plate.
[0139] 36. Parallelogram.
[0140] 37. Trapezoid.
[0141] 38. FIG. 8/Bar Bell.
[0142] 39. Bow Tie.
[0143] 40. Uneven Triangle.
[0144] The surface of one or more faces of the second portion may
be substantially smooth, i.e. may have indentations or protrusions
only at the microscopic level on the order of less than about 20
microns in width, depth, or height. Alternately the surface of one
or more faces the second portion may be textured, i.e. having
indentations or protrusions greater than about 20 microns, e.g.
greater than about 50 microns, or greater than about 100 microns,
or from about 1000 microns to about 30,000 microns in width, depth,
or height. In embodiments wherein the surface of one or more faces
the second portion is textured, the surface may contain an embossed
(raised) or debossed (indented) design. For example, the surface of
one or more faces the second portion may contain indentations,
intagliations, letters, symbols or a pattern such as a graphic or
logo. Alternatively, one or more faces of the second portion may
contain one or more depressions covering a substantial proportion
of its surface area, for example at least about 10%, or at least
about 20% or at least about 30% or at least about 50% of the
surface area of the face. One type of compressed tablets with
indentations in a major face are described for example in WO
01/85437, which describes a process for the production of tablets
with a cavity using a press. WO 99/6157 describes tablets,
compressed from a particulate material, having cavities to receive
an additional ingredient or mix of ingredients.
[0145] In one embodiment of the invention, a surface of the first
molded portion resides substantially conformally upon a surface of
the second portion. As used herein, "substantially conformally"
means that a surface of the first molded portion substantially
conforms inversely to the shape and texture of a surface of the
second portion, such that the first and second portions are in
substantial contact at the interface between them. As used herein,
"substantial contact" means that a major portion of the surface
area of at least one surface of the first portion is in contact
with a major portion of the surface area of at least one surface of
the second portion.
[0146] The dosage form of the invention may also incorporate
pharmaceutically acceptable adjuvants, including, for example,
preservatives, sweeteners such as aspartame, acesulfame potassium,
sucralose, and saccharin; flavors, antioxidants, surfactants, and
coloring agents.
[0147] In one embodiment, the dissolution characteristics of at
least one active ingredient meets USP specifications for immediate
release tablets containing the active ingredient. In embodiments in
which it is desired for the active ingredient to be absorbed into
the systemic circulation of an animal, the active ingredient or
ingredients are preferably capable of dissolution upon contact with
a fluid such as water, gastric fluid, intestinal fluid or the like.
For example, for acetaminophen tablets, USP 24 specifies that in pH
5.8 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at
least 80% of the acetaminophen contained in the dosage form is
released therefrom within 30 minutes after dosing, and for
ibuprofen tablets, USP 24 specifies that in pH 7.2 phosphate
buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of
the ibuprofen contained in the dosage form is released therefrom
within 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and
856 (1999). In another embodiment, the dissolution characteristics
of at least one active ingredient are modified: e.g. controlled,
sustained, extended, retarded, prolonged, delayed and the like. In
one particular embodiment, one portion of the dosage form provides
for immediate release of a first dose of an active ingredient
therefrom, and the other portion of the dosage form provides for
modified release of a second dose of either the same or a different
active ingredient contained therein.
[0148] The first portion of the dosage form of this invention
comprises a molded material. In a preferred embodiment, the molded
material may be obtained from flowable material. The flowable
material may be any edible material that is flowable at a
temperature between about 37.degree. C. and 250.degree. C., and
that is solid or can form a gel at a temperature between about
-10.degree. C. and about 35.degree. C. When it is in the fluid or
flowable state, the flowable material may comprise a dissolved or
molten component, and a solvent such as for example water. The
solvent may be partially or substantially removed by drying.
Suitable flowable materials include those comprising film forming
polymers, gelling polymers, hydrocolloids, low melting hydrophobic
materials such as fats and waxes, non-crystallizable carbohydrates,
and the like.
[0149] In one embodiment of the invention, the flowable material
comprises gelatin. Gelatin is a natural, thermogelling polymer. It
is a tasteless and colorless mixture of derived proteins of the
albuminous class which is ordinarily soluble in warm water. Two
types of gelatin--Type A and Type B--are commonly used. Type A
gelatin is a derivative of acid-treated raw materials. Type B
gelatin is a derivative of alkali-treated raw materials. The
moisture content of gelatin, as well as its Bloom strength,
composition and original gelatin processing conditions, determine
its transition temperature between liquid and solid. Bloom is a
standard measure of the strength of a gelatin gel, and is roughly
correlated with molecular weight. Bloom is defined as the weight in
grams required to move a half-inch diameter plastic plunger 4 mm
into a 6.67% gelatin gel that has been held at 10.degree. C. for 17
hours. In a preferred embodiment, the flowable material is an
aqueous solution comprising 20% 275 Bloom pork skin gelatin, 20%
250 Bloom Bone Gelatin, and approximately 60% water.
[0150] Other preferred flowable materials may comprise
sucrose-fatty acid esters; fats such as cocoa butter, hydrogenated
vegetable oil such as palm kernel oil, cottonseed oil, sunflower
oil, and soybean oil; mono- di- and triglycerides, phospholipids,
waxes such as carnuba wax, spermaceti wax, beeswax, candelilla wax,
shellac wax, microcrystalline wax, and paraffin wax; fat-containing
mixtures such as chocolate; sugar in the form on an amorphous glass
such as that used to make hard candy forms, crystallized sugar in a
supersaturated solution such as that used to make fondant forms;
carbohydrates such as sugar-alcohols (for example, sorbitol,
maltitol, mannitol, xylitol), or thermoplastic starch; and
low-moisture polymer solutions such as mixtures of gelatin and
other hydrocolloids at water contents up to about 30%, such as for
example those used to make "gummi" confection forms.
[0151] In one embodiment of the invention, the flowable material
may comprise a film former such as a cellulose ether, e.g.
hydroxypropylmethylcellulose or a modified starch, e.g. waxy maize
starch; optionally an extender, such as polycarbohydrates, e.g.
polydextrose or maltodextrin; optionally a thickener, such as a
hydrocolloid, e.g. xanthan gum or carrageenan, or a sugar, e.g.
sucrose; optionally a plasticizer, e.g. polyethylene glycol,
propylene glycol, vegetable oils such as castor oil, glycerin, and
mixtures thereof.
[0152] Any film former known in the art is suitable for use in the
flowable shell material of the present invention. Examples of
suitable film formers include, but are not limited to,
polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl
starch, hydroxyethyl starch, pullulan, methylethyl starch,
carboxymethyl starch, methylcellulose, hydroxypropylcellulose
(HPC), hydroxyethylmethylcellulose (HEMC),
hydroxypropylmethylcellulose (HPMC), hydroxybutylmethylcellulose
(HBMC), hydroxyethylethylcellulose (HEEC),
hydroxyethylhydroxypropylmethyl cellulose (HEMPMC), methacrylic
acid and methacrylate ester copolymers, polyethylene oxide and
polyvinylpyrrolidone copolymers, gelatin, proteins such as whey
protein, coaggulatable proteins such as albumin, casein, and casein
isolates, soy protein and soy protein isolates, pre-gelatinized
starches, and polymers and derivatives and mixtures thereof.
[0153] One suitable hydroxypropylmethylcellulose compound is HPMC
2910, which is a cellulose ether having a degree of substitution of
about 1.9 and a hydroxypropyl molar substitution of 0.23, and
containing, based upon the total weight of the compound, from about
29% to about 30% methoxyl and from about 7% to about 12%
hydroxylpropyl groups. HPMC 2910 is commercially available from the
Dow Chemical Company under the tradename METHOCEL E. METHOCEL E5,
which is one grade of HPMC-2910 suitable for use in the present
invention, has a viscosity of about 4 to 6 cps (4 to 6
millipascal-seconds) at 20.degree. C. in a 2% aqueous solution as
determined by a Ubbelohde viscometer. Similarly, METHOCEL E6, which
is another grade of HPMC-2910 suitable for use in the present
invention, has a viscosity of about 5 to 7 cps (5 to 7
millipascal-seconds) at 20.degree. C. in a 2% aqueous solution as
determined by a Ubbelohde viscometer. METHOCEL E15, which is
another grade of HPMC-2910 suitable for use in the present
invention, has a viscosity of about 15000 cps (15
millipascal-seconds) at 20.degree. C. in a 2% aqueous solution as
determined by a Ubbelohde viscometer. As used herein, "degree of
substitution" shall mean the average number of substituent groups
attached to a anhydroglucose ring, and "hydroxypropyl molar
substitution" shall mean the number of moles of hydroxypropyl per
mole anhydroglucose.
[0154] As used herein, "modified starches" include starches that
have been modified by crosslinking, chemically modified for
improved stability, or physically modified for improved solubility
properties. As used herein, "pre-gelatinized starches" or
"instantized starches" refers to modified starches that have been
pre-wetted, then dried to enhance their cold-water solubility.
Suitable modified starches are commercially available from several
suppliers such as, for example, A. E. Staley Manufacturing Company,
and National Starch & Chemical Company. One suitable modified
starch includes the pre-gelatinized waxy maize derivative starches
that are commercially available from National Starch & Chemical
Company under the tradenames PURITY GUM and FILMSET, and
derivatives, copolymers, and mixtures thereof. Such waxy maize
starches typically contain, based upon the total weight of the
starch, from about 0 percent to about 18 percent of amylose and
from about 100% to about 88% of amylopectin.
[0155] Suitable tapioca dextrins include those available from
National Starch & Chemical Company under the tradename CRYSTAL
GUM or K-4484, and derivatives thereof such as modified food starch
derived from tapioca, which is available from National Starch and
Chemical under the tradename PURITY GUM 40, and copolymers and
mixtures thereof.
[0156] Any thickener known in the art is suitable for use in the
film forming composition of the present invention. Examples of such
thickeners include but are not limited to hydrocolloids (also
referred to herein as gelling polymers) such as alginates, agar,
guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth,
pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan,
laminarin, scleroglucan, gum arabic, inulin, pectin, whelan,
rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, and
derivatives and mixtures thereof. Additional suitable thickeners
include crystallizable sugars, such as glucose (dextrose),
fructose, and the like, and derivatives and combinations
thereof.
[0157] Suitable xanthan gums include those available from C. P.
Kelco Company under the tradename, KELTROL 1000, XANTROL 180, or
K9B310.
[0158] Any plasticizer known in the pharmaceutical art is suitable
for use in the present invention, and may include, but not be
limited to polyethylene glycol; glycerin; sorbitol; triethyl
citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as
castor oil; surfactants such as polysorbates, sodium lauryl
sulfates, and dioctyl-sodium sulfosuccinates; propylene glycol;
mono acetate of glycerol; diacetate of glycerol; triacetate of
glycerol; natural gums and mixtures thereof. In solutions
containing a cellulose ether film former, an optional plasticizer
may be present in an amount, based upon the total weight of the
solution, from about 0% to about 40%.
[0159] The flowable material may optionally comprise adjuvants or
excipients, in which may comprise up to about 20% by weight of the
flowable material. Examples of suitable adjuvants or excipients
include detackifiers, humectants, surfactants, anti-foaming agents,
colorants, flavorants, sweeteners, opacifiers, and the like. In one
preferred embodiment, the flowable material comprises less than 5%
humectants, or alternately is substantially free of humectants,
such as glycerin, sorbitol, maltitol, xylitol, or propylene glycol.
Humectants have traditionally been included in pre-formed films
employed in enrobing processes, such as that disclosed in U.S. Pat.
Nos. 5,146,730 and 5,459,983, to ensure adequate flexibility or
plasticity and bondability of the film during processing.
Humectants function by binding water and retaining it in the film.
Pre-formed films used in enrobing processes can typically comprise
up to 45% water. Disadvantageously, the presence of humectant
prolongs the drying process, and can adversely affect the stability
of the finished dosage form.
[0160] In a preferred embodiment of the invention, the molded
material comprises at least about 80%; e.g. at least about 90% of a
material selected from film formers, gelling polymers
(hydrocolloids), low-melting hydrophobic materials,
non-crystallizable carbohydrates, and mixtures thereof. The molded
material may be formed by injection molding, advantageously
minimizing or eliminating the need for direct-compression
filler-binders such as microcrystalline cellulose, spray-dried
lactose, mineral salts such as calcium phosphate, crystalline
sugars such as sucrose, dextrates and the like. These materials
would disadvantageously detract from the clarity and stability of
the molded material. Preferably the molded material comprises less
than about 10%, e.g. less than about 1%, or less than about 0.1% of
direct-compression filler-binders.
[0161] In another embodiment, the molded material is prepared by
thermal setting molding using the method and apparatus described in
copending U.S. patent application Ser. No. 09/966,450, pages 57-63,
the disclosure of which is incorporated herein by reference. In
this embodiment, the molded material is formed by injecting a
starting material in flowable form into a molding chamber. The
starting material preferably comprises an active ingredient and a
thermal setting material at a temperature above the melting point
of the thermal setting material but below the decomposition
temperature of the active ingredient. The starting material is
cooled and solidifies in the molding chamber into a shaped form
(i.e. having the shape of the mold).
[0162] In another embodiment, the molded material is prepared by
thermal cycle molding using the method and apparatus described in
copending U.S. patent application Ser. No. 09/966,497, pages 27-51,
the disclosure of which is incorporated herein by reference. In
this embodiment, the molded material is formed by injecting a
starting material in flowable form into a heated molding chamber.
The starting material preferably comprises an active ingredient and
a thermoplastic material at a temperature above the set temperature
of the thermoplastic material but below the decomposition
temperature of the active ingredient. The starting material is
cooled and solidifies in the molding chamber into a shaped form
(i.e., having the shape of the mold).
[0163] According to this method, the starting material must be in
flowable form. For example, it may comprise solid particles
suspended in a molten matrix, for example a polymer matrix. The
starting material may be completely molten or in the form of a
paste. The starting material may comprise an active ingredient
dissolved in a molten material. Alternatively, the starting
material may be made by dissolving a solid in a solvent, which
solvent is then evaporated from the starting material after it has
been molded.
[0164] The starting material may comprise any edible material which
is desirable to incorporate into a shaped form, including active
ingredients such as those active ingredients described herein,
nutritionals, vitamins, minerals, flavors, sweeteners, and the
like. Preferably, the starting material comprises an active
ingredient and a thermal setting material. The thermal setting
material may be any edible material that is flowable at a
temperature between about 37 to about 250.degree. C., and that is a
solid at a temperature between about 0 to about -10.degree. C.
Preferred thermal setting materials include water-soluble polymers
such as polyalkylene glycols, polyethylene oxides and derivatives,
and sucrose esters; fats such as cocoa butter, hydrogenated
vegetable oil such as palm kernel oil, cottonseed oil, sunflower
oil, and soybean oil; mono- di- and triglycerides, phospholipids,
waxes such as carnuba wax, spermaceti wax, beeswax, candelilla wax,
shellac wax, microcrystalline wax, and paraffin wax; fat-containing
mixtures such as chocolate; sugar in the form on an amorphous glass
such as that used to make hard candy forms, crystallized
carbohydrates in a supersaturated solution such as that used to
make fondant forms; low-moisture polymer solutions such as mixtures
of gelatin and other hydrocolloids at water contents up to about
30% such as those used to make "gummi" confection forms. In a
particularly preferred embodiment, the thermal setting material is
a water-soluble polymer such as polyethylene glycol.
[0165] The first portion may be made in any shape or size. For
instance, irregularly shaped first portions may be made; i.e.
shapes having no more than one axis of symmetry. Cylindrically
shaped first portions may also be made. The molded material may be
prepared by any molding method, such as injection molding. In a
preferred embodiment, the molded material may be made using the
thermal setting method and apparatus described herein. In another
preferred embodiment of the invention, the molded material is
prepared by thermal cycle molding as described herein.
[0166] The first molded material and second material of the dosage
form of this invention are compositionally different. As used
herein, the term "compositionally different" means having features
that are readily distinguishable by qualitative or quantitative
chemical analysis, physical testing, or visual observation. For
example, the first and second materials may contain different
ingredients, or different levels of the same ingredients, or the
first and second materials may have different physical or chemical
properties, different functional properties, or be visually
distinct. Examples of physical or chemical properties that may be
different include hydrophylicity, hydrophobicity, hygroscopicity,
elasticity, plasticity, tensile strength, crystallinity, and
density. Examples of functional properties which may be different
include rate and/or extent of dissolution of the material itself or
of an active ingredient therefrom, rate of disintegration of the
material, permeability to active ingredients, permeability to water
or aqueous media, and the like. Examples of visual distinctions
include size, shape, topography, or other geometric features,
color, hue, opacity, and gloss.
[0167] In one embodiment, the second portion of the dosage form of
this invention comprises a compressed material. In one preferred
embodiment of this invention, the second portion is obtained by
compressing a powder. The powder may preferably comprise an active
ingredient and optionally contain various excipients, such as
binders, disintegrants, lubricants, fillers, glidants and the like,
as is conventional, or other particulate material of a medicinal or
non-medicinal nature, such as inactive placebo blends for
tableting, confectionery blends, and the like. In one embodiment,
the compressed second portion comprises active ingredient, powdered
wax (such as shellac wax, microcrystalline wax, polyethylene
glycol, and the like), and optionally disintegrants and lubricants
as are well known to those skilled in the art.
[0168] In one embodiment of the invention, the second portion is
obtained from a blend of powders having an average particle size of
about 50 to about 500 microns. In one embodiment, the active
ingredient has an average particle size of about 50 to about 500
microns. In another embodiment, at least one excipient has an
average particle size of about 50 to about 500 microns. In one such
embodiment, a major excipient, i.e. and excipient comprising at
least 50% by weight of the core, has an average particle size of
about 50 to about 500 microns. Particles in this size range are
particularly useful for direct compression processes.
[0169] In another embodiment of the invention, the second portion
is a directly compressed tablet, made from a powder which is
substantially free of water soluble polymeric binders and hydrated
polymers. This composition is advantageous for maintaining an
immediate release dissolution profile, minimizing processing and
material costs, and providing for optimal physical and chemical
stability of the dosage form.
[0170] Suitable excipients for use in a compressed portion include
fillers, binders, disintegrants, lubricants, glidants, and the
like.
[0171] Suitable fillers include water-soluble compressible
carbohydrates such as sugars, which include dextrose, sucrose,
maltose, and lactose, sugar-alcohols, which include mannitol,
sorbitol, maltitol, xylitol, starch hydrolysates, which include
dextrins, and maltodextrins, and the like, water insoluble
plasticly deforming materials such as microcrystalline cellulose or
other cellulosic derivatives, water-insoluble brittle fracture
materials such as dicalcium phosphate, tricalcium phosphate and the
like and mixtures thereof.
[0172] Suitable binders include dry binders such as polyvinyl
pyrrolidone, hydroxypropylmethylcellulose, and the like; wet
binders such as water-soluble polymers, including hydrocolloids
such as alginates, agar, guar gum, locust bean, carrageenan, tara,
gum arabic, tragacanth, pectin, xanthan, gellan, maltodextrin,
galactomannan, pusstulan, laminarin, scleroglucan, gum arabic,
inulin, pectin, whelan, rhamsan, zooglan, methylan, chitin,
cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics,
starches, and the like; and derivatives and mixtures thereof.
[0173] Suitable disintegrants include sodium starch glycolate,
cross-linked polyvinylpyrrolidone, cross-linked
carboxymethylcellulose, starches, microcrystalline cellulose, and
the like.
[0174] Suitable lubricants include long chain fatty acids and their
salts, such as magnesium stearate and stearic acid, talc, and
waxes.
[0175] Suitable glidants include colloidal silicon dioxide, and the
like.
[0176] In a preferred embodiment, the second portion is prepared by
the compression methods and apparatus described in copending U.S.
application Ser. No. 09/966,509, pages 16-27, the disclosure of
which is incorporated herein by reference. Specifically, the second
portion is made using a rotary compression module comprising a fill
zone, insertion zone, compression zone, ejection zone, and purge
zone in a single apparatus having a double row die construction as
shown in FIG. 6 of U.S. application Ser. No. 09/966,509. The dies
of the compression module are preferably filled using the
assistance of a vacuum, with filters located in or near each die.
The purge zone of the compression module includes an optional
powder recovery system to recover excess powder from the filters
and return excess powder to the dies.
[0177] In another embodiment of the invention, the first or second
portions, or both, may contain at least in part one or more
inserts. The inserts can be made in any shape or size. For
instance, irregularly shaped inserts can be made; i.e. shapes
having no more than one axis of symmetry. Cylindrically shaped
inserts may also be made. The insert may be prepared using
conventional techniques such as panning, compression, or molding.
In one embodiment, the insert is prepared using the thermal setting
method and apparatus as described herein.
[0178] In one embodiment of the invention, the insert or inserts
may have an average diameter from about 100 to about 1000 microns.
In another embodiment of this invention, the insert(s) may have an
average diameter or thickness from about 10% to about 90% of the
diameter or thickness of the dosage form, or portion thereof. In
yet another embodiment of this invention, the first or second
dosage form portion may comprise a plurality of inserts.
[0179] In another embodiment of the invention, the first portion,
second portion, or both may comprise a microelectronic device (e.g.
an electronic "chip") which may be used as an active component or
to control, for example, the rate of release of active ingredients
contained within the first and/or second portions or insert in
response to an input signal. Examples of such microelectronic
devices are as follows:
[0180] (1) Integrated, self-regulating responsive therapeutic
devices including biosensors, electronic feedback and
drug/countermeasure release devices which are fully integrated.
Such devices eliminate the need for telemetry and human
intervention, and are disclosed, for example, at
www.chiprx.com/products.html, which is incorporated herein by
reference;
[0181] (2) Miniaturized diagnostic imaging systems which comprise a
swallowable capsule containing a video camera, and are disclosed,
for example, at www.givenimaging.com/usa/default.asp, which is
incorporated herein by reference;
[0182] (3) Subcutaneous glucose monitors which comprise implantable
or insertable sensor devices which detect changes in glucose
concentration within intestinal fluid, and communicate to an
external detector and data storage device. Such devices are
disclosed, for example, at www.applied-medical.co.uk/glucose.htm,
which is incorporated herein by reference;
[0183] (4) Microdisplay vision aid devices encapsulated in an
artificial intraocular lens. Such devices include a receiver for
power supply, data and clock recovery, and a miniature LED array
flip-chip bonded to a silicon CMOS driver circuit and micro optics,
and are disclosed, for example, at
http://ios.oe.uni-duisberg.de/e/, which is incorporated herein by
reference. The microdisplay device receives a bit-stream+energy
wireless signal from a high dynamic range CMOS camera placed
outside the eye which generates a digital black & white picture
which is converted by a digital signal processing unit (DAP) into a
serial bit-stream with a data rate of approximately 1 Mbit/s. The
image is projected onto the retina;
[0184] (5) Microchips used to stimulate damaged retinal cells,
allowing them to send visual signals to the brain for patients with
macular degeneration or other retinal disorders. The chip is 2
mm.times.25 microns, and contains approximately 5,000 microscopic
solar cells ("microphotodiodes"), each with its own stimulating
electrode. These microphotodiodes convert the light energy from
images into electrical chemical impulses that stimulate the
remaining functional cells of the retina in patients with AMD and
RP. Such microchips are disclosed, for example, at
www.optobionics.com/artificialretina.htm, which is incorporated
herein by reference;
[0185] (6) Disposable "smart needles" for breast biopsies which
display results in real time. The device fits into a 20 to 21 gauge
disposable needle that is connected to a computer, as the needle is
inserted into the suspicious lesion. The device measures oxygen
partial pressure, electrical impedance, temperature, and light
scattering and absorption properties including deoxygenated
hemoglobin, vascularization, and tissue density. Because of the
accuracy benefits from the six simultaneous measurements, and
real-time nature of the device, it is expected to exceed the
accuracy levels achieved by the core needle biopsy procedure and
approach the high level of accuracy associated with surgical
biopsies. Further, if cancer is found, the device can be configured
to deliver various therapies such as cancer markers, laser heat,
cryogenics, drugs, and radioactive seeds. Such devices are
disclosed, for example, at www.bioluminate.com/description.html,
which is incorporated herein by reference; and
[0186] (7) Personal UV-B recorders, which are instrument grade
devices for measuring and recording UVB exposure and fit into a
wrist-watch face. They may also be worn as a patch.
[0187] In one preferred embodiment, the invention provides a dosage
form comprising a thermal cycle molded first portion and a
compressed powder second portion.
[0188] In another preferred embodiment, the invention provides a
dosage form comprising an injection molded first portion and a
compressed powder second portion.
[0189] In one embodiment of the invention, only the first portion
comprises one or more active ingredients. In another embodiment of
this invention, only the second portion comprises one or more
active ingredients. In yet another embodiment of this invention,
only the insert or inserts comprise one or more active ingredients.
In yet another embodiment of this invention, both the first and
second portions comprise one or more active ingredients. In yet
another embodiment of this invention, one or more of the first
portion, second portion or the insert or inserts comprise one or
more of the active ingredients. The active ingredient or
ingredients are preferably capable of dissolution upon contact with
a fluid such as water, gastric fluid, intestinal fluid or the
like.
[0190] In embodiments wherein one portion of the dosage form
comprises active ingredients, and another portion of the dosage
form is substantially free of active ingredients, the invention
advantageously enables a system of dosage form design with the
versatility to accomodate multiple different dosage amounts of
medication in the same size tablet, yet be readily identifiable to
patients and healthcare professionals in terms of its identity and
strength. For example, a particular medication may be commercially
available in several different strength dosage forms. It is
possible to design, using the present invention, a series of dosage
forms in which the second portion comprises active ingredient, and
varies in size according to the amount of active ingredient
contained therein. The molded first portion of the dosage form may
be substantially free of active ingredient, and may vary in size
inversely according the the size of the first portion, such that
the overall size of the dosage form remains constant for the
different strengths of active ingredient contained therein. In one
such embodiment, the two portions of the dosage forms may be
visually distinct. For example, the second portion of the dosage
form may be colored and/or opaque, and the first portion of the
dosage form may be colorless, transparent, semi-transparent or
translucent, thus providing visual reinforcement to both healthcare
professionals and patients as to the varying strengths of the
available dosage forms.
[0191] An overall understanding of the dosage form of this
invention may be obtained by reference to FIGS. 1A and 1B. In FIGS.
1A and 1B, a dosage form 2 is depicted which comprises a first
portion 8 comprising a molded material 10 and a second portion 4
comprising a compressed material 6. Material 10 and material 6 are
compositionally different. It will be understood that the shapes of
the first and second portions in FIGS. 1A and 1B are merely
illustrative, and are not meant to limit this invention in any
way.
[0192] Another embodiment of the invention is depicted in FIGS. 2A
and 2B, in which a dosage form 22 is depicted which comprises a
first portion 24 comprising a first molded material 26 and a second
molded material 27, and a second portion 28 comprising a compressed
material 30. Materials 26 and 27 are each are compositionally
different from material 30. It will be understood that the shapes
of the first and second portions in FIGS. 2A and 2B are merely
illustrative, and are not meant to limit this invention in any
way.
[0193] Another embodiment of the invention is depicted in FIGS. 3A
and 3B, in which dosage form 32 is depicted which comprises a first
portion 34 comprising a molded material 36, and a second portion 38
(shown in dashed outline in FIG. 3A) comprising a compressed
material 40. Material 36 is compositionally different from material
40. It will be understood that the shapes of the first and second
portions in FIGS. 3A and 3B are merely illustrative, and are not
meant to limit this invention in any way.
[0194] Another embodiment of the invention is depicted in FIGS. 4A
and 4B, in which dosage form 42 is depicted which comprises a first
portion 44 comprising a first molded material 46, and a second
portion 48 which is a molded insert which comprises a second molded
material 50. Material 46 is compositionally different from material
50. It will be understood that the shapes of the first and second
portions in FIGS. 4A and 4B are merely illustrative, and are not
meant to limit this invention in any way.
[0195] Another embodiment of the invention is depicted in FIGS. 5A
and 5B, in which dosage form 52 is depicted which comprises a first
portion 54 comprising a molded material 56, and a second portion 58
comprising a compressed material 60. Material 56 is compositionally
different from material 60. It will be understood that the shapes
of the first and second portions in FIGS. 5A and 5B are merely
illustrative, and are not meant to limit this invention in any
way.
[0196] Another embodiment of the invention is depicted in FIGS. 6A
and 6B, in which dosage form 62 is depicted which comprises a first
portion 64 comprising a molded material 66, and a second portion 68
comprising a compressed material 70. Material 66 is compositionally
different from material 70. It will be understood that the shapes
of the first and second portions in FIGS. 6A and 6B are merely
illustrative, and are not meant to limit this invention in any
way.
[0197] Another embodiment of the invention is depicted in FIGS.
7A-7C, in which dosage form 72 is depicted which comprises a first
portion 74 comprising a molded material 76, and a second portion 78
comprising a compressed material 80. Material 76 is compositionally
different from material 70. As shown in FIGS. 7B and 7C, first
portion 74 has projections 75 on one face thereof. It will be
understood that the shapes of the first and second portions in
FIGS. 7A-7C are merely illustrative, and are not meant to limit
this invention in any way.
[0198] Other embodiments of the invention are depicted in FIGS.
8A-8C. In FIG. 8A, dosage form 82 is depicted which comprises a
first portion 84 comprising a molded material 86, and a second
portion 88 comprising a compressed material 90. Material 86 is
compositionally different from material 90. In FIG. 8B, dosage form
182 is depicted which comprises a first portion 184 comprising a
molded material 186, and a second portion 188 comprising a
compressed material 190. Material 186 is compositionally different
from material 190. As shown in FIG. 8B, first portion 184 has a
tongue shaped portion 183 which interfaces with groove shaped
portion 185 of second portion 188. In FIG. 8C, dosage form 282 is
depicted which comprises a first portion 284 comprising a molded
material 286, and a second portion 288 comprising a compressed
material 290. Material 286 is compositionally different from
material 290. It will be understood that the shapes of the first
and second portions in FIGS. 8A-8C are merely illustrative, and are
not meant to limit this invention in any way.
[0199] Another embodiment of the invention is depicted in FIGS. 9A
and 9B, in which dosage form 92 is depicted which comprises a first
portion 94 comprising a molded material 96, and a second portion 98
comprising a compressed material 100. Material 96 is
compositionally different from material 100. It will be understood
that the shapes of the first and second portions in FIGS. 9A and 9B
are merely illustrative, and are not meant to limit this invention
in any way.
[0200] Another embodiment of this invention is depicted in FIG. 10,
in which dosage form 102 is depicted which comprises a first
portion 104 comprising a molded material 106, a second portion 108
comprising a compressed material 105, and a third portion 107 which
may comprise a molded or compressed material 109, preferably a
molded material. Material 106 is compositionally different from
material 105. Material 109 may be compositionally the same or
different than materials 106 or 105, although in the embodiment
depicted in FIG. 10 each of materials 106, 105 and 109 is
compositionally different from each other. In this embodiment,
either first portion 104 or second portion 108 or both contain an
active ingredient. Third portion 107 may act as a barrier to
prevent the passage there through of either or both the active
ingredients contained in first portion 104 or second portion 108.
It will be understood that the shapes of the first, second and
third portions in FIG. 10 are merely illustrative, and are not
meant to limit this invention in any way.
[0201] In one embodiment, the third portion has one or more major
faces. The third portion may be prepared by any suitable method,
for example it may be molded or compressed. The third portion may
have a variety of molded shapes, as described above with respect to
the first and second portions.
[0202] In one particular embodiment, the invention is a bi-layer
tablet in which the second portion is a compressed layer, the first
portion is a molded layer, and the interface between the compressed
and molded portions is a major tablet face.
[0203] The first molded material is substantially free of pores
having a diameter of 0.5-5.0 microns. As used herein,
"substantially free" means that the first molded material has a
pore volume of less than about 0.02 cc/g, preferably less than
about 0.01 cc/g, more preferably less than about 0.005 cc/g, in the
pore diameter range of 0.5 to 5.0 microns. Typical compressed
materials have pore volumes of more than about 0.02 cc/g in this
pore diameter range. In embodiments of this invention in which the
second or third portions comprise a molded material, the molded
material contained in the second or third portion likewise is
substantially free of pores having a diameter of 0.5 to 5.0
microns. Pore volume, pore diameter and density may be determined
using a Quantachrome Instruments PoreMaster 60 mercury intrusion
porosimeter and associated computer software program known as
"Porowin." The procedure is documented in the Quantachrome
Instruments PoreMaster Operation Manual. The PoreMaster determines
both pore volume and pore diameter of a solid or powder by forced
intrusion of a non-wetting liquid (mercury), which involves
evacuation of the sample in a sample cell (penetrometer), filling
the cell with mercury to surround the sample with mercury, applying
pressure to the sample cell by: (i) compressed air (up to 50 psi
maximum); and (ii) a hydraulic (oil) pressure generator (up to
60000 psi maximum). Intruded volume is measured by a change in the
capacitance as mercury moves from outside the sample into its pores
under applied pressure. The corresponding pore size diameter (d) at
which the intrusion takes place is calculated directly from the
so-called "Washburn Equation": d=-(4.gamma.(cos .O slashed.))/P
where .gamma. is the surface tension of liquid mercury, .O slashed.
is the contact angle between mercury and the sample surface and P
is the applied pressure.
[0204] Equipment used for pore volume measurements:
[0205] 1. Quantachrome Instruments PoreMaster 60.
[0206] 2. Analytical Balance capable of weighing to 0.0001 g.
[0207] 3. Desiccator.
[0208] Reagents used for measurements:
[0209] 1. High purity nitrogen.
[0210] 2. Triply distilled mercury.
[0211] 3. High pressure fluid (Dila AX, available from Shell
Chemical Co.).
[0212] 4. Liquid nitrogen (for Hg vapor cold trap).
[0213] 5. Isopropanol or methanol for cleaning sample cells.
[0214] 6. Liquid detergent for cell cleaning.
[0215] Procedure:
[0216] The samples remain in sealed packages or as received in the
dessicator until analysis. The vacuum pump is switched on, the
mercury vapor cold trap is filled with liquid nitrogen, the
compressed gas supply is regulated at 55 psi., and the instrument
is turned on and allowed a warm up time of at least 30 minutes. The
empty penetrometer cell is assembled as described in the instrument
manual and its weight is recorded. The cell is installed in the low
pressure station and "evacuation and fill only" is selected from
the analysis menu, and the following settings are employed:
[0217] Fine Evacuation time: 1 min.
[0218] Fine Evacuation rate: 10
[0219] Coarse Evacuation time: 5 min.
[0220] The cell (filled with mercury) is then removed and weighed.
The cell is then emptied into the mercury reservoir, and two
tablets from each sample are placed in the cell and the cell is
reassembled. The weight of the cell and sample are then recorded.
The cell is then installed in the low-pressure station, the
low-pressure option is selected from the menu, and the following
parameters are set:
[0221] Mode: Low pressure
[0222] Fine evacuation rate: 10
[0223] Fine evacuation until: 200% Hg
[0224] Coarse evacuation time: 10 min.
[0225] Fill pressure: Contact +0.1
[0226] Maximum pressure: 50
[0227] Direction: Intrusion And Extrusion
[0228] Repeat: 0
[0229] Mercury contact angle; 140
[0230] Mercury surface tension: 480
[0231] Data acquisition is then begun. The pressure vs. cumulative
volume-intruded plot is displayed on the screen. After low-pressure
analysis is complete, the cell is removed from the low-pressure
station and reweighed. The space above the mercury is filled with
hydraulic oil, and the cell is assembled and installed in the
high-pressure cavity. The following settings are used:
[0232] Mode: Fixed rate
[0233] Motor speed: 5
[0234] Start pressure: 20
[0235] End pressure: 60,000
[0236] Direction: Intrusion and extrusion
[0237] Repeat: 0
[0238] Oil fill length: 5
[0239] Mercury contact angle: 140
[0240] Mercury surface tension: 480
[0241] Data acquisition is then begun and graphic plot pressure vs.
intruded volume is displayed on the screen. After the high pressure
run is complete, the low-and high-pressure data files of the same
sample are merged.
[0242] In another embodiment of this invention, the composite
dosage form of the present invention may be coated with an
overcoating or shell.
[0243] In another embodiment of this invention, at least part of
the first portion extends below or penetrates through a surface of
the second portion to define a penetrated surface area of the
second portion. The area of the interface surfaces is substantially
the same, preferably at least 90%, of the penetrated surface
area.
[0244] In another embodiment of this invention, the area of the
interface surfaces is at least 10%, preferably 25%, more preferably
at least 50%, say greater than 90% of the area of a major face of
either the first or second portions.
[0245] In another embodiment of this invention, one face or side of
the second portion comprises a cavity, and the first portion is in
contact with the entire surface of the cavity.
[0246] A particular advantage of the present invention is that
either the first molded portion or second portion may be larger in
cross-section (in at least one location) than the opening to the
cavity within the second portion or first molded portion,
respectively, which receives the first portion or second portion.
In contrast, in the prior art an insert must be no larger in
cross-section than the opening of the cavity which receives the
insert. In a preferred embodiment of this invention, the first
molded portion or a part thereof is received by a cavity located
within the second portion. Thus, the first molded portion forms a
"tongue" which interlocks with the cavity or "groove" within the
second portion. This may also be expressed in terms of the "draft
angle" of the second portion. As used herein, the term "draft
angle" refers to the angle defined by the side wall of the cavity
and a line perpindicular to the face of the inserted (e.g. first)
portion, as described for example in Rosato et al., Injection
Molding Handbook, pp. 601-04, (2d ed. 1995), the disclosure of
which is incorporated herein by reference. In the present
invention, the draft angle of the second portion may have a value
less than zero. However, in the prior art compositions, the draft
angle must have a zero or positive value.
[0247] In another embodiment of this invention, at least one
exterior surface of the first portion is flush with at least one
exterior surface of the second portion.
[0248] This invention will be further illustrated by the following
examples, which are not meant to limit the invention in any
way.
EXAMPLE 1
[0249] Dosage forms of the invention are made in a continuous
process using an apparatus comprising a thermal cycle molding
module and a compression module linked in series via a transfer
device as described at pages 14-16 of copending U.S. application
Ser. No. 09/966,939, the disclosure of which is incorporated herein
by reference. The dosage forms have the structure shown in FIGS. 1A
and 1B and comprise a first portion comprising a first molded
material and a second portion comprising a second material that is
compressed.
[0250] The first portions are made of a flowable material
comprising the following ingredients:
1 Weight Mg/ Tablet Trade Name Manufacturer % Tablet Polyethylene
Carbowax .RTM. Union Carbide 60.3 190 Glycol 3350 Corporation,
Danbury, CT Croscarmellose Ac-Di-Sol .RTM. FMC Corporation, 30.1 95
Sodium Newark, DE Pseudoephedrine BASF 9.5 30 Hydrochloride
PharmaChemikalien Crystal GmbH & Co., Ludwigshafen/ Rhein.
[0251] The second portions are made of a dry blend comprising the
following ingredients: acetaminophen USP (590 mg/tablet), synthetic
wax X-2068 T20 (53 mg/tablet), sodium starch glycolate (EXPLOTAB)
(13.9 mg/tablet), silicon dioxide (0.6 mg/tablet), and magnesium
stearate NF (2.4 mg/tablet). The dry blend is compressed into
second portions on a compression module as described in copending
U.S. application Ser. No. 09/966,509 at pages 16-27 (incorporated
herein by reference). The compression module is a double row,
rotary apparatus, comprising a fill zone, insertion zone,
compression zone, ejection zone, and purge zone as shown in FIG. 6
of U.S. application Ser. No. 09/966,509. The dies of the
compression module are filled using vacuum assistance, with mesh
screen filters located in die wall ports of each die.
[0252] Second portions are transferred from the compression module
to the thermal cycle molding module via a transfer device. The
transfer device has the structure shown as 300 in FIG. 3 of
copending U.S. application Ser. No. 09/966,414, described at pages
51-57, incorporated herein by reference. It comprises a plurality
of transfer units 304 attached in cantilever fashion to a belt 312
as shown in FIGS. 68 and 69 of copending U.S. application Ser. No.
09/966,414. The transfer device rotates and operates in sync with
the thermal cycle molding module and compression module to which it
is coupled. Transfer units 304 comprise retainers 330 for holding
the second portions as they travel around the transfer device.
[0253] Next, first portions are produced and joined to the second
portions in the thermal cycle molding module, which has the general
structure shown in FIG. 3 of copending U.S. application Ser. No.
09/966,497. The thermal cycle molding module 200 comprises a rotor
202 around which a plurality of mold units 204 are disposed. The
thermal cycle molding module includes a reservoir 206 (see FIG. 4
of pending U.S. application Ser. No. 09/966,497) for holding the
material for making the first portions in flowable form. In
addition, the thermal cycle molding module is provided with a
temperature control system for rapidly heating and cooling the mold
units. FIGS. 55 and 56 of U.S. application Ser. No. 09/966,497
depict the temperature control system 600.
[0254] The thermal cycle molding module has the specific
configuration shown in FIG. 26A of copending U.S. application Ser.
No. 09/966,497. The thermal cycle molding module comprises center
mold assemblies 212 and upper mold assemblies 214 as shown in FIG.
26C of copending U.S. application Ser. No. 09/966,497, which mate
to form mold cavities. As rotor 202 rotates, second portions are
loaded into the center mold assemblies, and the opposing center and
upper mold assemblies close. Flowable material for making the first
portions, which is heated to a flowable state in reservoir 206, is
injected into the resulting mold cavities, which contain an empty
space adjacent to the second portions. First portions form in the
empty space. The temperature of the flowable material is then
decreased, hardening the flowable material into first portions
joined to the compressed second portions. The mold assemblies open
and eject the dosage forms.
[0255] Although this invention has been illustrated by reference to
specific embodiments, it will be apparent to those skilled in the
art that various changes and modifications may be made which
clearly fall within the scope of this invention.
* * * * *
References