U.S. patent application number 10/309730 was filed with the patent office on 2004-06-10 for surface treatment composition for soft substrates.
Invention is credited to Bunick, Frank J., Lin, Feng.
Application Number | 20040109889 10/309730 |
Document ID | / |
Family ID | 32312246 |
Filed Date | 2004-06-10 |
United States Patent
Application |
20040109889 |
Kind Code |
A1 |
Bunick, Frank J. ; et
al. |
June 10, 2004 |
Surface treatment composition for soft substrates
Abstract
A method for reducing the friability of soft substrates by
applying an effective amount of a water soluble, polymeric
dispersion to at least a portion of a treatment surface of the
substrate, such that less than about 90% of the exterior surface
has the dispersion applied thereto.
Inventors: |
Bunick, Frank J.; (Randolph,
NJ) ; Lin, Feng; (San Antonio, TX) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
32312246 |
Appl. No.: |
10/309730 |
Filed: |
December 4, 2002 |
Current U.S.
Class: |
424/465 |
Current CPC
Class: |
A61K 9/2072 20130101;
A61K 9/286 20130101; A61K 9/0056 20130101; A61K 9/2866
20130101 |
Class at
Publication: |
424/465 |
International
Class: |
A61K 009/20 |
Claims
We claim:
1. A treated pharmaceutical substrate comprised of: a) a soft
pharmaceutical substrate having a hardness value of no more than
about 15 kp/cm.sup.2 and comprised of an exterior surface having an
exterior surface area, said exterior surface comprised of at least
one treatable surface; and b) a pharmaceutically-acceptable, water
dispersible polymer layer in contact with at least a portion of
said treatable surface to form a treated surface, wherein said
treated surface has a total surface area that is less than the
total exterior surface area of the exterior surface, and the
treated pharmaceutical substrate possesses a friability factor of
at least about 2.
2. The treated pharmaceutical substrate of claim 1 wherein the
treated pharmaceutical substrate contains from about 3 .mu.g to
about 20 .mu.g of polymer per square millimeter of treated
surface.
3. The treated pharmaceutical substrate of claim 1 wherein the
treated pharmaceutical substrate contains from about 5 .mu.g to
about 9 .mu.g of polymer per square millimeter of treated
surface.
4. The treated pharmaceutical substrate of claim 1 wherein the
surface area of the treated surface is, based upon the exterior
surface area of the exterior surface, from about 10% to about
90%.
5. The treated pharmaceutical substrate of claim 1 wherein the
surface area of the treated surface is, based upon the exterior
surface area of the exterior surface, from about 20% to about
50%.
6. The treated pharmaceutical substrate of claim 1 wherein the soft
pharmaceutical substrate has a hardness value from about 1
kp/cm.sup.2 to about 8 kp/cm.sup.2 prior to application of the
dispersion and the treated pharmaceutical substrate has a hardness
value of no more than about 8 kp/cm.sup.2.
7. The treated pharmaceutical substrate of claim 6 wherein the soft
pharmaceutical substrate has a hardness value from about 1
kp/cm.sup.2 to about 5 kp/cm.sup.2 prior to application of the
dispersion and the treated pharmaceutical substrate has a hardness
value of no more than about 5 kp/cm.sup.2.
8. The treated pharmaceutical substrate of claim 1 having a
friability factor of at least about 3.
9. The treated pharmaceutical substrate of claim 8 having a
friability factor of at least about 5.
10. The treated pharmaceutical substrate of claim 1, wherein the
polymeric dispersion is comprised of film forming polymers, gelling
polymers, adhesive polymers, and derivatives, copolymers, and
mixtures thereof.
11. The treated pharmaceutical substrate of claim 10, wherein in
the polymeric dispersion is comprised of polyvinylalcohol (PVA),
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 copolymers, methacrylate ester copolymers, polyvinyl alcohol
and polyethylene glycol copolymers, proteins such as whey protein,
egg albumin, casein, casein isolates, soy protein and soy protein
isolates, pre-gelatinized starches, corn syrup solids, film-forming
modified starches, and copolymers, derivatives and mixtures
thereof.
12. The treated pharmaceutical substrate of claim 11, wherein the
polymeric dispersion comprises at least one polymer selected from
the group consisting of hydroxypropylmethylcellulose,
hydroxypropylcellulose, polyvinyl alcohol and polyethylene glycol
copolymer hydroxypropyl starch, corn syrup solids, maltodextrin,
pullulan, gelatin, and tapioca dextrin and copolymers, derivatives
and mixtures thereof.
13. The treated pharmaceutical substrate of claim 1, wherein the
soft pharmaceutical substrate contains an active agent selected
from the group consisting of acetaminophen, ibuprofen,
pseudoephedrine, famotidine, or pharmaceutically acceptable salts
thereof, and mixtures thereof.
14. The treated pharmaceutical substrate of claim 1, wherein the
treatable surface is a first land having a first surface and a
second land having a second surface, and the polymeric layer is in
contact with at least a portion of said first surface and/or said
second surface.
15. The treated pharmaceutical substrate of claim 1, wherein the
treatable surface is a rim having a rim surface, and the polymeric
layer is in contact with at least a portion of the rim surface.
16. The treated pharmaceutical substrate of claim 1, wherein the
treatable surface is bellyband having a bellyband surface, and the
polymeric layer is in contact with at least a portion of said
bellyband surface.
17. The treated pharmaceutical substrate of claim 1, wherein the
treatable surface is a face having a face surface, and the
polymeric layer is in contact with at least a portion of said face
surface.
18. A method for reducing the friability of a soft pharmaceutical
substrate having a hardness value of no more than about 15
kp/cm.sup.2, said soft pharmaceutical substrate comprised of an
exterior surface having at least one treatable surface, comprised
of: applying an effective amount of a pharmaceutically-acceptable,
water dispersible polymeric dispersion to at least a portion of
said treatable surface to yield a treated pharmaceutical substrate,
wherein said treatable surface has a total surface area that is
smaller than the total exterior surface area of the exterior
surface, and the treated pharmaceutical substrate possesses a
friability factor of at least about 2.
19. The method of claim 18 wherein the friability is at least about
3.
20. The method of claim 18 wherein the friability is at least about
5.
21. The method of claim 18 wherein the treated pharmaceutical
substrate contains from about 3 .mu.g to about 20 .mu.g of polymer
per squared millimeter of treated surface.
22. The method of claim 18 wherein the treated pharmaceutical
substrate contains from about 5 .mu.g to about 9 .mu.g of polymer
per squared millimeter of treated surface.
23. The method of claim 18 wherein the surface area of the treated
surface is, based upon the exterior surface area of the exterior
surface, from about 10% to about 90%.
24. The method of claim 18 wherein the surface area of the treated
surface is, based upon the exterior surface area of the exterior
surface, from about 20% to about 50%.
25. The method of claim 18 wherein the soft pharmaceutical
substrate has a hardness value from about 1 kp/cm.sup.2 to about 8
kp/cm.sup.2 prior to application of the dispersion and the treated
pharmaceutical substrate has a hardness value of no more than about
8 kp/cm.sup.2.
26. The method of claim 18 wherein the soft pharmaceutical
substrate has a hardness value from about 1 kp/cm.sup.2 to about 5
kp/cm.sup.2 prior to application of the dispersion and the treated
pharmaceutical substrate has a hardness value of no more than about
5 kp/cm.sup.2.
27. The method of claim 18, wherein the polymer comprises at least
one polymer selected from the group consisting of
hydroxypropylmethylcellulos- e, hydroxypropylcellulose, polyvinyl
alcohol and polyethylene glycol copolymer hydroxypropyl starch,
corn syrup solids, maltodextrin, pullulan, gelatin, and tapioca
dextrin, and derivatives, and copolymers thereof.
28. A treated immediate-release pharmaceutical substrate comprised
of: a) a soft pharmaceutical substrate having a hardness value of
no more than about 15 kp/cm.sup.2 and comprised of an exterior
surface having an exterior surface area, said exterior surface
comprised of at least one treatable surface; and b) a
pharmaceutically-acceptable polymer layer in contact with at least
a portion of said treatable surface to form a treated surface,
wherein said treated surface has a total surface area that is
smaller than the total exterior surface area of the exterior
surface, and the treated pharmaceutical substrate possesses
immediate release properties and a friability factor of at least
about 2.
29. A treated pharmaceutical substrate comprised of: a) a soft
pharmaceutical substrate having a hardness value of no more than
about 15 kp/cm.sup.2 and comprised of an exterior surface having an
exterior surface area, said exterior surface comprised of at least
one treatable surface; and b) a pharmaceutically-acceptable, water
dispersible polymer layer in contact with at least a portion of
said treatable surface to form a treated surface, wherein the
weight of said water dispersible polymer layer is not more than
about 0.5% of the weight of the untreated substrate, and the
treated pharmaceutical substrate possesses a friability factor of
at least about 2.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a surface treatment composition
for soft substrates, and methods for preparing and applying the
same.
BACKGROUND OF THE INVENTION
[0002] Soft dosage forms are widely used in a variety of consumer
products. For example, many soft confections have been marketed
with commercial success due to consumer preference. Further,
pharmaceutical manufacturers have also developed oral dosage forms
that provide alternatives to the traditional, swallowable solid
tablets. These alternative dosage forms, which for example include
chewable or orally disintegrable tablets, are often easier and more
convenient to administer, especially to pediatric and geriatric
patients. Softer tablets are also advantageous for applications
where it is desirable to provide for the topical availability of an
active ingredient in the mouth or throat to provide either local
effects or systemic absorption.
[0003] In chewable dosage forms, active ingredients are often
employed in the form of particles that are coated with tastemasking
polymers. Such dosage forms, which possess an easier "bite-through"
and superior tastemasking performance, are prepared by employing
reduced compaction pressures during manufacture. Although the
resulting dosage forms are generally softer, they also are
disadvantageously more fragile, brittle, and thus more easily
chipped. This increased fragility, or friability of soft tablets
adds cost and complexity to handling and packaging of these dosage
forms.
[0004] In disintegratable dosage forms, the dosage form is designed
to disintegrate in the mouth without chewing. See, e.g., U.S. Pat.
Nos. 5,464,632, 5,223,264 and 5,178,878. While these soft tablets
advantageously disintegrate completely in the mouth prior to
swallowing, they also have the disadvantage of being highly
friable. Thus, this dosage form also requires costly specialized
handling and packaging in order to prevent breakage.
[0005] Known methods for reducing the friability of soft chewable
or disintegrable tablets include incorporation of low-melting
materials in the tablet matrix. PCT Application No. WO 93/13758,
for example, describes soft tablets comprising a meltable binder
distributed throughout the tablet, which has been melted and
solidified to improve the strength (e.g. hardness and friability)
of the tablets. U.S. Pat. No. 4,327,076 discloses a soft,
breakage-resistant chewable tablet compressed from particles
comprising a fatty material. U.S. Pat. No. 6,258,381 describes a
tablet made from a granular agglomerate comprising a mixture of at
least one active ingredient and a binder. After the granular
agglomerate is heated to melt the binder only at or near the tablet
surface it is then cooled in order to solidify the melted binder
into a substantially continuous phase. This results in the
formation of a fused layer on the outside of the tablet, which
reduces its friability. U.S. Pat. No. 6,277,409 describes a soft
chewable tablet coated with a molten material, which is then
solidified to form a protective coating that reduces the friability
of the soft tablet. Although these processes yield tablets having
the consumer-preferred soft tablet core and reduced friability, the
high levels of coating material employed are economically
disadvantageous.
[0006] Swallowable tablets are commonly coated with film coatings
or polymeric coatings, such as those comprising cellulose
derivatives, in order to improve their swallowability. These
coatings typically surround the entire surface of the tablet.
However, the coatings typically employed for swallowable tablets
are not particularly suitable for use on chewable tablets or those
designed to disintegrate in the oral cavity because they would
hinder the dissolution, disintegration, chewability, and
organoleptic characteristics, such as mouthfeel of such soft
tablets.
[0007] It is also known in the art to apply an impermeable coating
on only a portion of the dosage form for the purpose of controlling
the surface area through which active ingredient is released from
the dosage form. See, e.g. U.S. Pat. No. 5,922,342. According to
one embodiment of this method, a desired modified, controlled, or
substantially constant, or "zero-order", dissolution rate is
provided on the tablets by controlling the surface area of contact
between the core and dissolution medium. See for example, U.S. Pat.
Nos. 3,146,169; 3,851,638; 4,663,147; 4,816,262; and 6,110,500.
Typical manufacturing methods for these types of dosage forms
include making a core, coating the core with impermeable material,
then removing a portion of the core and coating to create the area
for drug dissolution. See, e.g., U.S. Pat. No. 4,803,076 (tablet
press for use in the manufacture of a truncated cone-shaped, as
well as an apparatus for removal of a portion of the coated dosage
form.). Generally, a substantial level of coating is required in
these types of controlled release applications in order for the
coating to function as an impermeable barrier to the passage of
water and/or active ingredient therethrough. Due to the dissolution
rate designed for these tablets, such impermeable coatings are not
only unsuitable for immediate release applications, but they are
only intended for use on hard, swallowable tablets.
[0008] A need, therefore, exists for soft, immediate release
tablets that have a pleasant taste as well as low friability
properties, which may be processed with standard bulk handling
equipment and packaged in bottles.
SUMMARY OF THE INVENTION
[0009] The present invention comprises, consists of, and/or
consists essentially of a treated pharmaceutical substrate
comprised of, consisting of, and/or consisting essentially of:
[0010] a) a soft pharmaceutical substrate having a hardness value
of no more than about 15 kp/cm.sup.2 and comprised of an exterior
surface having an exterior surface area, said exterior surface
comprised of at least one treatable surface; and
[0011] b) a pharmaceutically-acceptable, water dispersible polymer
layer in contact with at least a portion of said treatable surface
to form a treated surface,
[0012] wherein said treated surface has a total surface area that
is less than the total exterior surface area of the exterior
surface, and the treated pharmaceutical substrate possesses a
friability factor of at least about 2.
[0013] Another embodiment of the present invention is directed to a
method for reducing the friability of a soft pharmaceutical
substrate having a hardness value of no more than about 15
kp/cm.sup.2, said soft pharmaceutical substrate comprised of an
exterior surface having at least one treatable surface, comprised
of, consisting of, and/or consisting essentially of:
[0014] applying an effective amount of a
pharmaceutically-acceptable, water dispersible polymeric dispersion
to at least a portion of said treatable surface to yield a treated
pharmaceutical substrate,
[0015] wherein said treatable surface has a total surface area that
is smaller than the total exterior surface area of the exterior
surface, and the treated pharmaceutical substrate possesses a
friability factor of at least about 2.
[0016] Yet another embodiment of the present invention is directed
to a treated immediate-release pharmaceutical substrate comprised
of, consisting of, and/or consisting essentially of:
[0017] a) a soft pharmaceutical substrate having a hardness value
of no more than about 15 kp/cm.sup.2 and comprised of an exterior
surface having an exterior surface area, said exterior surface
comprised of at least one treatable surface; and
[0018] b) a pharmaceutically-acceptable polymer layer in contact
with at least a portion of said treatable surface to form a treated
surface,
[0019] wherein said treated surface has a total surface area that
is smaller than the total exterior surface area of the exterior
surface, and the treated pharmaceutical substrate possesses
immediate release properties and a friability factor of at least
about 2.
[0020] Yet another embodiment of the present invention is directed
to a treated pharmaceutical substrate comprised of, consisting of,
and/or consisting essentially of:
[0021] a) a soft pharmaceutical substrate having a hardness value
of no more than about 15 kp/cm.sup.2 and comprised of an exterior
surface having an exterior surface area, said exterior surface
comprised of at least one treatable surface; and
[0022] b) a pharmaceutically-acceptable, water dispersible polymer
layer in contact with at least a portion of said treatable surface
to form a treated surface,
[0023] wherein the weight of said water dispersible polymer layer
is not more than about 0.5% of the weight of the untreated
substrate, and the treated pharmaceutical substrate possesses a
friability factor of at least about 2.
[0024] Advantageously the friability of the soft substrates treated
in accordance with the present invention is significantly reduced
without affecting their pleasant taste. Due to their reduction in
friability, such treated soft substrates may be processed with
standard bulk handling equipment and packaged in bottles.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1A is an enlarged, perspective view of a flat-faced,
round tablet.
[0026] FIG. 1B is an enlarged top plan view of the tablet of FIG.
1A., the bottom plan view being identical thereto;
[0027] FIG. 1C is an enlarged side view of the tablet of FIG.
1A.
[0028] FIG. 2A is an enlarged, perspective view of a flat-faced,
squared tablet.
[0029] FIG. 2B is an enlarged top plan view of the tablet of FIG.
2A., the bottom plan view being identical thereto;
[0030] FIG. 2C is an enlarged side view of the tablet of FIG.
2A.
[0031] FIG. 3A is an enlarged, perspective view of a flat-faced,
triangular tablet.
[0032] FIG. 3B is an enlarged top plan view of the tablet of FIG.
3A., the bottom plan view being identical thereto;
[0033] FIG. 3C is an enlarged side view of the tablet of FIG.
3A.
[0034] FIG. 4A is an enlarged, perspective view of a flat-faced,
hexagonal tablet.
[0035] FIG. 4B is an enlarged top plan view of the tablet of FIG.
4A., the bottom plan view being identical thereto;
[0036] FIG. 4C is an enlarged side view of the tablet of FIG.
4A.
[0037] FIG. 5A is an enlarged, perspective view of a bi-convexed
faced, round tablet having a ledge.
[0038] FIG. 5B is an enlarged top plan view of the tablet of FIG.
5A., the bottom plan view being identical thereto;
[0039] FIG. 5C is an enlarged side view of the tablet of FIG.
5A.
[0040] FIG. 5D is a further enlarged view of the land as
illustrated in FIG. 5C.
[0041] FIG. 6A is an enlarged, perspective view of a bi-convexed
faced, oblong caplet.
[0042] FIG. 6B is an enlarged top plan view of the caplet of FIG.
6A., the bottom plan view being identical thereto;
[0043] FIG. 6C is an enlarged side view of the caplet of FIG.
6A.
[0044] FIG. 7A is a perspective view of the tablet of FIG. 1A,
having a polymeric dispersion application at both faces and both
rims.
[0045] FIG. 7B is a perspective view of the tablet of FIG. 1A,
having a polymeric dispersion application at the bellyband and both
rims.
[0046] FIG. 7C is a perspective view of the tablet of FIG. A,
having a polymeric dispersion application at the upper face and
one-half of the upper rim, and at the lower face and one half of
the lower rim (not shown).
[0047] FIG. 7D is a perspective view of the tablet of FIG. 1A,
having a polymeric dispersion application at the bellyband, and at
one-half of the upper rim and one-half of the lower rim.
[0048] FIG. 7E is a perspective view of the tablet of FIG. 1A,
having a polymeric dispersion application at both rims.
[0049] FIG. 8A is an enlarged, cross-sectional view of a substrate
having a polymeric layer residing upon at least a portion of its
treatable surface.
[0050] FIG. 8B is an enlarged, cross-sectional view of a substrate
having a polymeric layer residing at at least a portion of its
treatable surface.
[0051] FIG. 8C is an enlarged, cross-sectional view of a substrate
having a polymeric layer residing immediately beneath at least a
portion of its treatable surface.
DETAILED DESCRIPTION OF THE INVENTION
[0052] For purposes herein the term, "substrate" refers to a
surface, layer or underlying base or support upon which another
substance resides or acts, and the term, "vulnerable edge" is any
substrate edge, that is particularly susceptible to mechanical
damage. The term, "rim," shall include a vulnerable edge on a
substrate, which is defined during compaction (also referred to as
"compression") via a contact region between an upper or lower punch
face and a die wall, and an overlap area. "Overlap area," as used
herein, shall mean a width of the substrate surface on either side
of a vulnerable edge; although the size of the overlap area is not
critical, it typically ranges from about 0 mm to about 2.0 mm, e.g.
from about 0 mm to about 1.0 mm, in width on either side of the
vulnerable edge. As illustrated in FIG. 2, the tablet possesses two
rims 11, 11', each of which includes a vulnerable edge 18 and an
overlap area 15 (shown in part), as well as four side vulnerable
edges 12 (shown in part), each of which includes a vulnerable edge
17 and an overlap area 15'.
[0053] As illustrated in FIG. 1, "belly band," as used herein,
shall mean a substrate surface 2, that is defined during compaction
via contact with a die wall and includes one-half of the overlap
area of the upper rim 5 and one-half of the overlap area of the
lower rim 5'. "Face," as used herein, is the portion 3 of a
compressed tablet formed by the upper and lower punch faces, and
includes one-half of the overlap area of a rim 5". As illustrated
in FIG. 5, "land," as used herein, is a planar substrate surface
43, 43' around the perimeter of a convex portion of a substrate
face bearing one or more convex surfaces, and includes the rim 115.
The land is formed by the perimeter of the punch face during
compaction. "Treatable Surface," as used herein, shall mean any
surface of the substrate that includes at least a portion of a
vulnerable edge so long as the total treatable surface area is from
about 10% to about 90% of the total substrate surface area.
Examples of treatable surfaces include the rim, belly band, face,
and/or the land, or portions thereof.
[0054] As used herein, the term "dosage form" applies to any
composition designed to contain a specific pre-determined amount
(dose) of a certain ingredient, such as, for example, an active
ingredient as defined below. Suitable dosage forms include those
suitable for oral administrations including, but not limited to,
pharmaceutical drug delivery systems, or compositions for
delivering minerals, vitamins and other nutraceuticals, oral care
agents, flavorants, and the like.
[0055] As used herein, the term "immediate release" shall mean that
the dissolution of the active ingredient contained in the dosage
form conforms to USP specifications for immediate release tablets
containing the particular active ingredient employed. 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).
[0056] In one embodiment, the dosage form may be an orally
administered system for delivering a pharmaceutical active
ingredient to the gastro-intestinal tract of a human, or
alternatively to the mouth or throat for localized activity,
topical absorption, or systemic absorption through the oral,
buccal, or pharyngeal mucosa. In another embodiment, the dosage
form may be an orally administered "placebo" system consisting
essentially of pharmaceutically inactive ingredients, which is
designed to have the same visual appearance as a particular
pharmaceutically active dosage form. Such "placebo" system dosage
forms are suitable for use as control dosage forms in clinical
studies, and in particular, those studies designed for testing the
safety and efficacy of a particular pharmaceutically active
ingredient.
[0057] "Tablets," as used herein, refer to compressed or molded
solid dosage forms of any shape or size. "Water soluble" or "water
solubilize," as used herein in connection with non-polymeric
materials, shall mean from sparingly soluble to very soluble, i.e.,
not more than 100 parts water required to dissolve 1 part of the
non-polymeric, water soluble solute. See Remington, "The Science
and Practice of Pharmacy," pages 208-209 (2000). "Water soluble" or
"water solubilize," as used herein in connection with polymeric
materials, shall mean that the polymer swells in water and can be
dispersed at the molecular level to form a homogeneous dispersion
or colloidal solution. "Water dispersible," as used herein in
connection with polymeric materials, shall mean at least a portion
of the polymer is removed from the dosage form within 60 minutes
after immersion of the dosage form in an aqueous medium such as
that used for in-vitro dissolution testing, or gastrointestinal
fluids.
[0058] "Hardness" as used herein in connection with dosage forms
indicates the resistance of the dosage form to breaking in response
to a diametrically applied stress. Hardness is a term used in the
art to describe the diametrical breaking strength as measured by
the conventional pharmaceutical hardness testing equipment, such as
a Vector-Schleuniger Hardness Tester. In order to compare values
across different size tablets, the breaking strength is normalized
for the area of the break, which may be approximated as (tablet
diameter x thickness). This normalized value, expressed in
kp/cm.sup.2, is sometimes referred to in the art as "tablet tensile
strength." A general discussion of tablet hardness testing is found
in Leiberman et al., Pharmaceutical Dosage Forms--Tablets, Volume
2, 2.sup.nd ed., Marcel Dekker Inc., 1990, pp. 213-217, 327-329,
which is incorporated by reference herein.
[0059] The substrate of the present invention may be any edible
solid or semi-solid composition having at least one vulnerable
edge. In certain embodiments, the substrate has one or more major
faces. Substrates suitable for use in the present invention may be
of any size or shape. For example, in one embodiment the substrate
may be in the shape of a truncated cone. In other embodiments the
substrate may be shaped as a polyhedron, such as a cube, pyramid,
prism, or the like; or may have the geometry of a space figure with
some non-flat faces, such as a cone, cylinder, sphere, torus, or
the like. Exemplary substrate shapes which may be employed include
tablet shapes formed from compaction 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 compaction tooling):
[0060] 1. Shallow Concave.
[0061] 2. Standard Concave.
[0062] 3. Deep Concave.
[0063] 4. Extra Deep Concave.
[0064] 5. Modified Ball Concave.
[0065] 6. Standard Concave Bisect.
[0066] 7. Standard Concave Double Bisect.
[0067] 8. Standard Concave European Bisect.
[0068] 9. Standard Concave Partial Bisect.
[0069] 10. Double Radius.
[0070] 11. Bevel & Concave.
[0071] 12. Flat Plain.
[0072] 13. Flat-Faced-Beveled Edge (F.F.B.E.).
[0073] 14. F.F.B.E. Bisect.
[0074] 15. F.F.B.E. Double Bisect.
[0075] 16. Ring.
[0076] 17. Dimple.
[0077] 18. Ellipse.
[0078] 19. Oval.
[0079] 20. Capsule.
[0080] 21. Rectangle.
[0081] 22. Square.
[0082] 23. Triangle.
[0083] 24. Hexagon.
[0084] 25. Pentagon.
[0085] 26. Octagon.
[0086] 27. Diamond.
[0087] 28. Arrowhead.
[0088] 29. Bullet.
[0089] 30. Barrel.
[0090] 31. Half Moon.
[0091] 32. Shield.
[0092] 33. Heart.
[0093] 34. Almond.
[0094] 35. House/Home Plate.
[0095] 36. Parallelogram.
[0096] 37. Trapezoid.
[0097] 38. FIG. 8/Bar Bell.
[0098] 39. Bow Tie.
[0099] 40. Uneven Triangle.
[0100] Illustrative examples of some substrate shapes are shown in
FIGS. 1-6. FIGS. 1A through 1C illustrate a flat-faced, round
substrate 100 having an upper face 3, a lower face (not shown), an
upper rim 1, a lower rim 1', and a belly band 2. FIGS. 2A through
2C illustrate a squared, flat-faced substrate 200 having an upper
face 13, a lower face (not shown), a four-sided bellyband 7 (not
all sides shown), four side vulnerable edges 12, an upper rim 11,
and lower rim 11'. Each of the side vulnerable edges includes a
vulnerable edge 17 and an overlap area 15' on each of the two
adjacent bellyband sides. FIGS. 3A through 3C illustrate a
triangular, flat-faced substrate 300 having an upper face 23 (one
side shown), a lower face (not shown), a three-sided bellyband 27
(not all sides shown), an upper rim 21, a lower rim 21', and three
side vulnerable edges 22. Each of the side vulnerable edges
includes a vulnerable edge 22' and an overlap area 25 on each of
the two adjacent bellyband sides. FIGS. 4A through 4C illustrate a
hexagonal, flat-faced substrate having an upper face 33, lower face
(not shown), a six-sided bellyband 37 (not all sides shown), upper
rim 31, lower rim 31', and six vulnerable side edges 32. Each of
the side vulnerable edges includes a vulnerable edge 32' and an
overlap area 35 on each of the two adjacent bellyband sides. FIGS.
5A through 5D illustrate a bi-convex, round substrate 500 having an
upper face 44, lower face, 44', upper rim 41', lower rim 41",
bellyband 42, an upper land 43', and lower land 43".
[0101] FIGS. 6A through 6C illustrate an oblong convex substrate
600 having two oppositely positioned convex faces 155, 155', and a
bellyband 160 therebetween (shown most clearly in FIGS. 6A and 6C).
As shown in FIG. 6A, the substrate 600 has an upper land 430, a
lower land 430', an upper rim 210, and a lower rim 210'.
[0102] Substrates suitable for use in the present invention may
contain one or more active ingredients. The term "active
ingredient" is used herein in a broad sense and may encompass any
material that can be carried by or entrained in the system. For
example, the active ingredient can be a pharmaceutical,
nutraceutical, vitamin, dietary supplement, nutrient, herb,
foodstuff, dyestuff, nutritional, mineral, supplement, oral care
agent or favoring agent or the like and combinations thereof.
[0103] Suitable oral care agents include breath fresheners, tooth
whiteners, antimicrobial agents, tooth mineralizers, tooth decay
inhibitors, topical anesthetics, mucoprotectants, and the like.
[0104] Suitable flavoring agents include menthol, peppermint, mint
flavors, fruit flavors, chocolate, vanilla, bubblegum flavors,
coffee flavors, liqueur flavors and combinations and the like.
[0105] Suitable pharmaceutical active ingredients useful herein can
be selected from classes from those in the following therapeutic
categories: ace-inhibitors; alkaloids; antacids; analgesics;
anabolic agents; anti-anginal drugs; anti-allergy agents;
anti-arrhythmia agents; antiasthmatics; antibiotics;
anticholesterolemics; anticonvulsants; anticoagulants;
antidepressants; antidiarrheal preparations; anti-emetics;
antihistamines; antihypertensives; anti-infectives;
anti-inflammatories; antilipid agents; antimanics; anti-migraine
agents; antinauseants; antipsychotics; antistroke agents;
antithyroid preparations; anabolic drugs; antiobesity agents;
antiparasitics; antipsychotics; antipyretics; antispasmodics;
antithrombotics; antitumor agents; antitussives; antiulcer agents;
anti-uricemic agents; anxiolytic agents; appetite stimulants;
appetite suppressants; beta-blocking agents; bronchodilators;
cardiovascular agents; cerebral dilators; chelating agents;
cholecystekinin antagonists; chemotherapeutic agents; cognition
activators; contraceptives; coronary dilators; cough suppressants;
decongestants; deodorants; dermatological agents; diabetes agents;
diuretics; emollients; enzymes; erythropoietic drugs; expectorants;
fertility agents; fungicides; gastrointestinal agents; growth
regulators; hormone replacement agents; hyperglycemic agents;
hypoglycemic agents; ion-exchange resins; laxatives; migraine
treatments; mineral supplements; mucolytics, narcotics;
neuroleptics; neuromuscular drugs; non-steroidal anti-inflammatory
drugs (NSAIDs); nutritional additives; peripheral vasodilators;
polypeptides; prostaglandins; psychotropics; renin inhibitors;
respiratory stimulants; sedatives; steroids; stimulants;
sympatholytics; thyroid preparations; tranquilizers; uterine
relaxants; vaginal preparations; vasoconstrictors; vasodilators;
vertigo agents; vitamins; wound healing agents; and others.
[0106] In certain embodiments the active ingredient may be selected
from the group of pharmaceuticals consisting of analgesics,
anti-inflammatory agents, antiarthritics, anesthetics,
antihistamines, antitussives, antibiotics, anti-infective agents,
antivirals, anticoagulants, antidepressants, antidiabetic agents,
antiemetics, antiflatulents, antifungals, 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.
[0107] 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.
[0108] 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.
[0109] In one embodiment of the invention, the gastrointestinal
agents may be selected from bisacodyl, famotadine, ranitidine,
cimetidine, prucalopride, diphenoxylate, loperamide, lactase,
mesalamine, bismuth, antacids, and pharmaceutically acceptable
salts, esters, isomers, and mixtures thereof.
[0110] In another embodiment, the active ingredient is selected
from analgesics, anti-inflammatories, and antipyretics, which
included but are not limited to non-steroidal anti-inflammatory
drugs (NSAIDs) including: 1) propionic acid derivatives, i.e., e.g.
ibuprofen, naproxen, and ketoprofen; 2) acetic acid derivatives,
i.e., e.g. indomethacin, diclofenac, sulindac, and tolmetin; 3)
fenamic acid derivatives, i.e., e.g. mefanamic acid, meclofenamic
acid, and flufenamic acid; 4) biphenylcarbodylic acid derivatives,
i.e., e.g. diflunisal and flufenisal; and 5) oxicams, i.e., e.g.
piroxicam, sudoxicam, isoxicam, and meloxicam.
[0111] In one embodiment, the active ingredient is a propionic acid
derivative NSAID selected from ibuprofen, naproxen, flurbiprofen,
fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen,
carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically
acceptable salts, derivatives, and combinations thereof.
[0112] In another embodiment of the invention, the active
ingredient is an analgesic selected from acetaminophen, acetyl
salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen,
diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and
pharmaceutically acceptable salts, esters, isomers, and mixtures
thereof.
[0113] In yet another embodiment of the invention, the active
ingredient is a respiratory agent selected from pseudoephedrine,
phenylpropanolamine, chlorpheniramine, dextromethorphan,
diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine,
cetirizine, mixtures thereof and pharmaceutically acceptable salts,
esters, isomers, and mixtures thereof.
[0114] Examples of particular active ingredients that may be used
in the invention include, but are not limited to: acetaminophen;
acetic acid; acetylsalicylic acid, including its buffered forms;
acrivastine; albuterol and its sulfate; alcohol; alkaline
phosphatase; allantoin; aloe; aluminum acetate, carbonate,
chlorohydrate and hydroxide; alprozolam; amino acids; aminobenzoic
acid; amoxicillin; ampicillin; amsacrine; amsalog; anethole;
ascorbic acid; aspartame; astemizole; atenolol; azatidine and its
maleate; bacitracin; balsam peru; BCNU (carmustine); beclomethasone
diproprionate; benzocaine; benzoic acid; benzophenones; benzoyl
peroxide; benzquinamide and its hydrochloride; bethanechol; biotin;
bisacodyl; bismuth subsalicylate; bornyl acetate; bromopheniramine
and its maleate; buspirone; caffeine; calamine; calcium carbonate,
casinate and hydroxide; camphor; captopril; cascara sagrada; castor
oil; cefaclor; cefadroxil; cephalexin; centrizine and its
hydrochloride; cetirizine; cetyl alcohol; cetylpyridinium chloride;
chelated minerals; chloramphenicol; chlorcyclizine hydrochloride;
chlorhexidine gluconate; chloroxylenol; chloropentostatin;
chlorpheniramine and its maleates and tannates; chlorpromazine;
cholestyramine resin; choline bitartrate; chondrogenic stimulating
protein; cimetidine; cinnamedrine hydrochloride; citalopram; citric
acid; clarithromycin; clemastine and its fumarate; clonidine;
clorfibrate; cocoa butter; cod liver oil; codeine and its fumarate
and phosphate; cortisone acetate; ciprofloxacin HCl;
cyanocobalamin; cyclizine hydrochloride; cyproheptadine; danthron;
dexbromopheniramine maleate; dextromethorphan and its hydrohalides;
diazepam; dibucaine; dichloralphenazone; diclofen and its alkali
metal sales; diclofenac sodium; digoxin; dihydroergotamine and its
hydrogenates/mesylates; diltiazem; dimethicone; dioxybenzone;
diphenhydramine and its citrate; diphenhydramine and its
hydrochloride; divalproex and its alkali metal salts; docusate
calcium, potassium, and sodium; doxycycline hydrate; doxylamine
succinate; dronabinol; efaroxan; enalapril; enoxacin; ergotamine
and its tartrate; erythromycin; estropipate; ethinyl estradiol;
ephedrine; epinephrine bitartrate; erythropoietin; eucalyptol;
famotidine; fenoprofen and its metal salts; ferrous fumarate,
gluconate and sulfate; fexofenadine; fluoxetine; folic acid;
fosphenytoin; 5-fluorouracil (5-FU); fluoxetine; flurbiprofen;
furosemide; gabapentan; gentamicin; gemfibrozil; glipizide;
glycerine; glyceryl stearate; granisetron; griseofulvin; growth
hormone; guafenesin; hexylresorcinol; hydrochlorothiazide;
hydrocodone and its tartrates; hydrocortisone and its acetate;
8-hydroxyquinoline sulfate; hydroxyzine and its pamoate and
hydrochloride salts; ibuprofen; indomethacin; inositol; insulin;
iodine; ipecac; iron; isosorbide and its mono- and dinitrates;
isoxicam; ketamine; kaolin; ketoprofen; lactic acid; lanolin;
lecithin; leuprolide acetate; lidocaine and its hydrochloride salt;
lifinopril; liotrix; loperamide, loratadine; lovastatin;
luteinizing hormore; LHRH (lutenizing hormone replacement hormone);
magnesium carbonate, hydroxide, salicylate, and trisilicate;
meclizine; mefenamic acid; meclofenamic acid; meclofenamate sodium;
medroxyprogesterone acetate; methenamine mandelate; menthol;
meperidine hydrochloride; metaproterenol sulfate; methscopolamine
and its nitrates; methsergide and its maleate; methyl nicotinate;
methyl salicylate; methyl cellulose; methsuximide; metoclopramide
and its halides/hydrates; metronidazole; metoprotol tartrate;
miconazole nitrate; mineral oil; minoxidil; morphine; naproxen and
its alkali metal sodium salts; nifedipine; neomycin sulfate;
niacin; niacinamide; nicotine; nicotinamide; nimesulide;
nitroglycerine; nonoxynol-9; norethindrone and its acetate;
nystatin; octoxynol; octoxynol-9; octyl dimethyl PABA; octyl
methoxycinnamate; omega-3 polyunsaturated fatty acids; omeprazole;
ondansetron and its hydrochloride; oxolinic acid; oxybenzone;
oxtriphylline; para-aminobenzoic acid (PABA); padimate-O;
paramethadione; pentastatin; peppermint oil; pentaerythritol
tetranitrate; pentobarbital sodium; perphenazine; pheneizine
sulfate; phenindamine and its tartrate; pheniramine maleate;
phenobarbital; phenol; phenolphthalein; phenylephrine and its
tannates and hydrochlorides; phenylpropanolamine; phenytoin;
pirmenol; piroxicam and its salts; polymicin B sulfate; potassium
chloride and nitrate; prazepam; procainamide hydrochloride;
procaterol; promethazine and its hydrochloride; propoxyphene and
its hydrochloride and napsylate; pramiracetin; pramoxine and its
hydrochloride salt; prochlorperazine and its maleate; propanolol
and its hydrochloride; promethazine and its hydrochloride;
propanolol; pseudoephedrine and its sulfates and hydrochlorides;
pyridoxine; pyrolamine and its hydrochlorides and tannates;
quinapril; quinidine gluconate and sulfate; quinestrol; ralitoline;
ranitadine; resorcinol; riboflavin; salicylic acid; scopolamine;
sesame oil; shark liver oil; simethicone; sodium bicarbonate,
citrate, and fluoride; sodium monofluorophosphate; sucralfate;
sulfanethoxazole; sulfasalazine; sulfur; sumatriptan and its
succinate; tacrine and its hydrochloride; theophylline;
terfenadine; thiethylperazine and its maleate; timolol and its
maleate; thioperidone; tramadol; trimetrexate; triazolam;
tretinoin; tetracycline hydrochloride; tolmetin; tolnaftate;
triclosan; trimethobenzamide and its hydrochloride; tripelennamine
and its hydrochloride; tripolidine hydrochloride; undecylenic acid;
vancomycin; verapamil HCl; vidaribine phosphate; vitamins A, B, C,
D, B.sub.1, B.sub.2, B.sub.6, B.sub.12, E, and K; witch hazel;
xylometazoline hydrochloride; zinc; zinc sulfate; zinc
undecylenate. Active ingredients may further include, but are not
limited to food acids; insoluble metal and mineral hydroxides,
carbonates, oxides, polycarbophils, and salts thereof; adsorbates
of active drugs on a magnesium trisilicate base and on a magnesium
aluminum silicate base, and mixtures thereof. Mixtures and
pharmaceutically acceptable salts of these and other actives can be
used.
[0115] The amount of active ingredient to be used in the substrate
will depend upon several factors such as, for example, the desired
active ingredient and the desired dosing requirements, and can be
readily determined by one skilled in the art without undue
experimentation.
[0116] Substrates suitable for use in the present invention
typically include those suitable for administration as a soft
dosage form, i.e. those having a hardness value that permits
comfortable chewing and dissolving in the mouth. In one embodiment,
the hardness of the untreated soft dosage form is no more than
about 15 kiloponds per square centimeter (kp/cm.sup.2), e.g., from
about 1 kp/cm.sup.2 to about 8 kp/cm.sup.2, or from about 1
kp/cm.sup.2 to about 5 kp/cm.sup.2. Soft dosage forms having such
low hardness values often possess a friability of more than about
2% when measured using the rotating drop method specified by the
United States Pharmacopoeia 23, Chapter <1216>, p. 1981
(1995), which is incorporated by reference herein.
[0117] The substrates may be made in any manner, and for tablet
dosage forms, a variety of tableting methods are known in the art.
Conventional methods for tablet production include direct
compression ("dry blending"), dry granulation followed by
compression (i.e. compaction), and wet granulation followed by
drying and compression (i.e. compaction). Other methods include the
use of compacting roller technology such as a chilsonator or drop
roller, or molding, casting, or extrusion technologies. All of
these methods are well known in the art, and are described in
detail in, for example, Lachman, et al., The Theory and Practice of
Industrial Pharmacy, Chapter 11, (3 Ed. 1986), which is
incorporated by reference herein.
[0118] In the "direct compression" tableting method, a blend of the
active ingredient and any other appropriate optional ingredients
are directly compacted. After all ingredients are blended together,
a pre-determined volume of particles from the blend is filled into
a die cavity of a rotary tablet press, which continuously rotates
as part of a "die table" from the filling position to a compaction
position to an ejection position. At the compaction position, the
particles are compacted between an upper punch and a lower punch.
At the ejection position, the resulting tablet is pushed from the
die cavity by the lower punch and guided to an ejection chute by a
stationary "take-off" bar.
[0119] Soft substrates suitable for use in the present invention
may be produced via methods known in the art such as, for example,
molding or compaction. In general, soft tablets may also be made by
direct compaction of a mixture of tableting ingredients, including
an active ingredient, and various excipients, such as binders,
flavorants, lubricants, etc. The mixture is fed into a die cavity
of a tablet press and a tablet is formed by applying pressure. The
hardness of the resulting soft tablet is a direct function of the
compaction pressure employed and the compactability of the
ingredients in the formulation, and is typically up to about 15
kiloponds per square centimeter (kp/cm.sup.2.
[0120] In one embodiment of the present invention, the compressed,
chewable tablet may be prepared by dry blending the active
ingredient, a water-disintegratable, compressible carbohydrate such
as, for example, lactose, sorbitol and/or sucrose, and other
optional ingredients, then compressing the mixture into the desired
shape of a dosage form having a hardness of about 1
kp/cm.sup.2.
[0121] If the active ingredient has an objectionable taste, it may
be coated with a known taste masking coating. Examples of suitable
taste masking coatings, and methods for their production, are
described in U.S. Pat. Nos. 4,851,226, 5,075,114, and 5,489,436,
which are all incorporated by reference herein. Other 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. Such coaccervation-encapsulated
acetaminophen may be purchased commercially from Eurand America,
Inc. Vandalia, Ohio, or from Circa Inc., Dayton, Ohio.
[0122] In accordance with the present invention, a portion of the
exterior surface of the substrates is treated with a polymeric
dispersion. The polymeric dispersion suitable for use in the
present invention is comprised of, based upon the total weight
percent of the dispersion, from more than about 0% to about 25%,
for example, from greater than about 0% to about 10%, from greater
than about 0% to about 5%, or from greater than about 0% to about
2%, of a dispersible polymer, and from about 75% to about less than
100% of a solvent.
[0123] Dispersible polymers suitable for use in the present
invention include, but are not limited to film forming polymers,
gelling polymers, adhesive polymers, and derivatives, copolymers,
and mixtures thereof. In one embodiment, the dispersible polymers
are water soluble. The dispersible polymers are also suitable for
immediate release dosage forms, which means that the dissolution of
one or more active ingredients contained in dosage form conforms to
USP specifications for immediate release tablets containing the
particular active ingredient employed.
[0124] Examples of suitable film forming polymers for use in the
present invention, include, but are not limited to,
polyvinylalcohol (PVA), 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 copolymers, methacrylate ester
copolymers, polyvinyl alcohol and polyethylene glycol copolymers,
proteins such as whey protein, egg albumin, casein, casein
isolates, soy protein and soy protein isolates, pre-gelatinized
starches, corn syrup solids, film-forming modified starches, and
copolymers, derivatives and mixtures thereof. Preferred film
forming polymers for use in the present invention include
hydroxypropylcellulose, hydroxypropylmethylcellulose, and
copolymers and mixtures thereof.
[0125] 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. As used herein, "degree of substitution"
shall mean the average number of substituent groups attached to an
anhydroglucose ring, and "hydroxypropyl molar substitution" shall
mean the number of moles of hydroxypropyl per mole anhydroglucose.
HPMC 2910 is commercially available from the Dow Chemical Company
under the tradename, "Methocel E."
[0126] "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.
[0127] One suitable polyvinyl alcohol and polyethylene glycol
copolymer is commercially available from BASF Corporation under the
tradename "Kollicoat IR".
[0128] As used herein, "modified starches" include starches that
have been modified via crosslinking and/or other chemical
modification for improved stability or optimized performance, or
physical modification for improved solubility properties or
optimized performance. Examples of chemically-modified starches are
well known in the art and typically include those starches that
have been chemically treated to cause replacement of some of its
hydroxyl groups with either ester or ether groups. Crosslinking, as
used herein, may occur in modified starches when two hydroxyl
groups on neighboring starch molecules are chemically linked. As
used herein, "pre-gelatinized starches" or "instantized starches"
refers to physically 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.
[0129] A suitable film forming 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
percent to about 88 percent of amylopectin.
[0130] Another suitable film forming modified starch includes the
hydroxypropylated starches, in which some of the hydroxyl groups of
the starch have been etherified with hydroxypropyl groups, usually
via treatment with propylene oxide. One example of a suitable
hydroxypropyl starch that possesses film-forming properties is
available from Grain Processing Company under the tradename,
"Pure-Cote B790".
[0131] Suitable film forming 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.
[0132] Another suitable film forming material derived from starch
is corn syrup solids, which is commercially available from National
Starch and Chemical under the trademark, "N-Tack"; derivatives
thereof; copolymers thereof; and mixtures thereof.
[0133] Any gelling polymer known in the art is suitable for use in
the present invention. Examples of such gelling polymers include
but are not limited to hydrocolloids such as alginates, agar, guar
gum, locust bean gum, kappa carrageenan, iota carrageenan, tara,
gum arabic, tragacanth, pectin, xanthan gum, gellan gum,
maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,
gum arabic, inulin, pectin, whelan, rhamsan, zooglan, methylan,
chitin, chitosan; gelling starches such as acid hydrolyzed starches
and derivatives and mixtures thereof.
[0134] Suitable xanthan gums include those available from C.P.
Kelco Company under the tradename, "Keltrol 1000," "Xantrol 180,"
or "K9B310."
[0135] "Gelling starches," as used herein, include those starches
that, when combined with water and heated to a temperature
sufficient to form a solution, thereafter form a gel upon cooling
to a temperature below the gelation point of the starch. Examples
of gelling starches include, but are not limited to, acid
hydrolyzed starches such as that available from Grain Processing
Corporation under the tradename, "Pure-Set B950"; hydroxypropyl
distarch phosphate such as that available from Grain Processing
Corporation under the tradename, "Pure-Gel B990", and mixtures
thereof.
[0136] "Acid-hydrolyzed starch," as used herein, is one type of
modified starch that results from treating a starch suspension with
dilute acid at a temperature below the gelatinization point of the
starch. During the acid hydrolysis, the granular form of the starch
is maintained in the starch suspension, and the hydrolysis reaction
is ended by neutralization, filtration and drying once the desired
degree of hydrolysis is reached. As a result, the average molecular
size of the starch polymers is reduced. Acid-hydrolyzed starches
(also known as "thin boiling starches") tend to have a much lower
hot viscosity than the same native starch as well as a strong
tendency to gel when cooled.
[0137] Any adhesive polymer known in the art is suitable for use in
the present invention. Examples of such adhesive polymers include,
but are not limited to, polysaccharides such as maltodextrin,
polydextrose, and mucilagee; proteins such as gelatin, whey
protein, and albumin, and derivatives and combinations thereof.
[0138] Examples of solvents suitable for use in the present
invention include, but are not limited to, water; water-miscible
polar organic solvents such as methanol, ethanol, isopropanol, and
acetone; non-water miscible organic solvents such as methylene
chloride, methylethylketone, methylisobutylketone, chloraform,
benzene, toluene, pentane, and hexane; and derivatives and mixtures
thereof.
[0139] In one embodiment, the polymer dispersion is substantially
free of adjuvants or modifiers such as plasticizers, dispersion
aids, welting agents, stabilizers, preservatives, and the like. By
substantially free, it is meant that the polymer dispersion
contains, based upon the total weight of the polymer dispersion,
less than about 5%, e.g. less than about 1% of adjuvants or
modifiers.
[0140] The polymeric dispersion may be prepared by dispersing the
dispersable polymer in the solvent under suitable conditions to
uniformly disperse the polymer at the molecular level. In one
embodiment wherein the solvent is water, the polymeric dispersion
may be prepared by heating water to a temperature effective for
solubilizing the polymer. Although the temperature and quantity of
water may depend on, for example, the solubility of the polymer
selected, typically the required temperature may range from about
room temperature to about 90.degree. C. The dispersible polymer may
then be added to the heated water, with stirring, until all of the
polymer is dissolved therein. The resulting solution is cooled to
ambient temperature and, if necessary, further diluted with an
additional amount of room temperature water in order to achieve the
desired solution concentration.
[0141] The polymeric dispersion of the present invention may be
applied to various types of substrates, especially those that are
soft and/or are highly friable. Examples of such treated substrates
may nonexclusively result products such as pharmaceutical dosage
forms, confectionary products, nutritional supplements, food
stuffs, dyestuffs, and dietary supplements
[0142] In accordance with the present invention, an effective
amount of the polymeric dispersion of the present invention may be
applied to the surface of the substrate such that the overall
friability of the treated substrate is reduced by a factor of at
least about 2, e.g. at least about 2.5, at least about 3, or at
least about 5, relative to the friability of the uncoated
substrate. Such a reduction in friability may be achieved by
applying the composition of the present invention to at least a
portion of a vulnerable edge such that less than all of the
exterior substrate surface, e.g. from about 10% to about 90%, from
about 20% to about 80% or from about 20% to about 50% of the
exterior substrate surface, has been treated with the polymeric
dispersion.
[0143] In one embodiment, the polymeric dispersion is primarily
applied to at least a portion of: 1) one or more of the rims; 2)
the belly band; 3) one or more of the face(s); 4) and/or one or
more of the land(s), with the remainder of the substrate having no
polymeric dispersion applied thereto.
[0144] The areas of a flat, disk-shaped tablet onto which a
polymeric dispersion may be applied are illustrated in FIGS. 7A
through 7E, and further explained in Table A below:
1TABLE A Areas For Polymeric Dispersion Application FIGURE AREAS
NUMBER ON TABLET TO WHICH DISPERSION IS APPLIED 7A Two faces
(including two rims) 7B Belly band (including two rims) 7C Two
faces (including one-half of a rim/face) 7D Belly band (including
one-half of an upper rim and one-half of a lower rim) 7E Two
rims
[0145] When the polymeric dispersion is applied to a vulnerable
edge on the substrate, the resulting treatment area includes both
that vulnerable edge as well as an overlap area. Hence, the
quantity of substrate surface area receiving treatment may be
approximated by relating about 1 linear millimeter of vulnerable
edge to about 2 square millimeters of treated substrate surface.
See, for example, FIG. 2, which exemplifies that treatment of the
rim includes an overlap area 15. For substrates that do not bear
substantial opposing planar surfaces, such as, for example, the
biconvex shape of FIG. 5, the polymeric dispersion may be applied
on the upper land 43' and/or the lower land 43" in a similar
fashion such that an effective amount of the dispersion enrobes and
includes one-half of the upper rim 41' and/or one-half of the lower
rim 41", respectively, in an overlap area 115.
[0146] One skilled in the art may readily appreciate that the
location and size of the substrate surface area on which the
polymeric dispersion treatment is applied may vary depending upon,
for example, the nature of the substrate surface, the thickness of
the polymeric dispersion application, the shape of the substrate,
and the dimensions of the substrate.
[0147] The quantity of polymeric dispersion applied to the
substrate will depend upon a number of factors including, but not
limited to, the concentration of the polymer in the dispersion, the
desired thickness of the application on the substrate, the hardness
of the substrate surface, and the dimension of the substrate
surfaces. However, in order to obtain a friability reduction factor
(as defined in Table B) of at least about 2, the polymeric
dispersion should be applied to at least one treatment surface
location such that the substrate possesses a polymer layer of from
about 3 micrograms/mm.sup.2 to about 20 micrograms/mm.sup.2, e.g.
from about 4 micrograms/mm.sup.2 to about 12 micrograms/mm.sup.2 or
from about 5 micrograms/mm.sup.2 to about 9
micrograms/mm.sup.2.
[0148] The composition of the present invention may be applied to a
substrate by any method well known in the art. Such methods may
include, but are not limited to, the use of a wet roller, a brush,
or a spray nozzle, and are disclosed in, for example, U.S. Pat. No.
5,922,342, which is incorporated by reference herein
[0149] In one embodiment, the substrate may be removably secured to
a rotation means, and the polymeric dispersion may then be applied
to the desired treatment surface location on the rotating
substrate.
[0150] Although the temperature and pressure conditions for
applying the polymeric dispersion to the substrate will vary
dependent upon several factors such as, for example, the type of
polymers selected, in general the temperature may range from about
20.degree. C. to about 90.degree. C., e.g. from about 25.degree. C.
to 65.degree. C. For example, in polymeric dispersions containing
HPMC, the polymeric dispersion is generally applied to the
substrate at a temperature of less than about 90.degree. C. because
HPMC is not soluble in water at higher temperatures.
[0151] After the polymeric dispersion is applied to the desired
treatment surface on the substrate, the treated substrate may then
be dried in order to evaporate the solvent from the composition and
to set the polymer. The desired drying temperature and setting time
may vary depending upon, for example, the type of polymer selected,
the solvent employed, and the concentration of polymeric dispersion
employed, and would readily be appreciated by one having ordinary
skill in the art without undue experimentation.
[0152] The treated substrate produced in accordance with the
present invention possesses a polymeric layer that is in contact
with the treatable surface of the substrate. As used herein, "in
contact with" shall mean that the layer resides upon, and/or
resides at, and/or resides immediately beneath, at least a portion
of the treatable surface, and "immediately beneath," as used herein
shall mean within a location that is less than about 2 mm inwards
from the treatable surface. For example, the polymeric dispersion
may penetrate the treatable surface to the extent that the formed
polymer layer both resides immediately beneath the treatable
surface as well as at the treatable surface. FIG. 8A represents a
cross-sectional view of a substrate 900 possessing a polymeric
layer 901 that resides upon at least a portion of the treatable
surface 902. FIG. 8B represents a cross-sectional view of a
substrate 900 possessing a polymeric layer 901 residing at a
portion of the treatable surface 902. FIG. 8C is a cross-sectional
view of a substrate 900 possessing a polymeric layer 901
immediately beneath at least a portion of the treatable surface
902. The depth of penetration of the applied polymeric dispersion
may depend upon a number of factors such as, for example, the
hardness of the substrate.
[0153] Advantageously, substrates treated with polymeric
dispersions in accordance with the present invention do not incur
an increase in hardness that is substantially perceptible to the
user. In addition, such treated substrates incur a negligible
weight gain, i.e., e.g., a post-drying gain of less than about
0.5%. In one embodiment, the weight of the water dispersible
polymer layer is not more than about 0.5%, e.g. not more than about
0.25%, say not more than about 0.1% of the weight of the untreated
substrate.
[0154] Surprisingly, we have also found that when the polymeric
dispersion is applied predominantly to the treatable surfaces, so
that from about 10% to about 90% of the overall substrate surface
has been treated with the polymeric dispersion of the present
invention, the overall friability of the substrate is reduced by a
factor of at least about 2. Because a consumer would not perceive
the addition of the small quantity of composition thereto, this
reduction in friability occurs without a sacrifice in organoleptic
characteristics, such as mouthfeel. In one embodiment, the tablets
of the present invention posses a fast melt-away charasteric
because their disintegration and dissolution in the oral cavity are
not hindered by the presence of a coating.
[0155] Another substantial advantage of this invention is that it
permits low hardness substrates to be subsequently coated with one
or more additional coatings (e.g. film-coatings) using processes
that may have otherwise destroyed the integrity of such substrates
but for the treatment in accordance with the present invention.
[0156] Yet another substantial advantage of this invention is
apparent in the use of the polymeric dispersion in immediate
release dosage forms. More specifically, because the polymeric
dispersion is water dispersible, a reduction in friability of the
substrate can be achieved without detriment to its immediate
release properties of the substrate.
[0157] The invention illustratively disclosed herein suitably may
be practiced in the absence of any component, ingredient, or step
that is not specifically disclosed herein. An example is set forth
below to further illustrate the nature of the invention and the
manner of carrying it out. However, the invention should not be
considered as being limited to the details thereof.
EXAMPLES
Example 1
Preparation HPMC Surface Treatment Solution
[0158] A surface treatment solution having the components set forth
below was prepared as follows:
2 Coating solution ingredients: Deionized water 100 mL HPMC* 5.0 g
*Methocel HPMC E5" available from Dow Corning.
[0159] 30 mL of deionized water was placed into a beaker and heated
to 90.degree. C. on a hot plate. After adding 5.0 grams of HPMC
powder thereto, with stirring and under constant temperature, 50 mL
of deionized water, having a temperature of 25.degree. C., was then
added thereto with stirring until all of the HPMC was dissolved.
The resulting solution was then diluted to volume with deionized
water at room temperature in a 100 mL volumetric flask.
Example 2
Application of HPMC Surface Treatment Solution to Substrate
Rims
[0160] A round, flat-faced, beveled edge tablet, which was
commercially available from McNEIL-PPC, Inc. under the tradename,
"MOTRIN Jr. Strength," was selected from a batch with an average
hardness value of 2.57 kp/cm.sup.2. The tablet, which had a height
of approximately 5.56 mm and a radius of approximately 12 mm,
weighed about 770 mg. The tablet was fixed to a 1/4 inch wooden
dowel attached to an inverted mixer (Model RW-20 DZM,
Janke&Kunkel, IKA-Works, Inc.) with a small quantity of
mounting putty (Manco Inc.). The mixer was set to rotate the dowel
and substrate at approximately 30 rpm.
[0161] An artist's brush having a total bristle width of
approximately 3 mm was wetted with the solution of Example 1 and
applied continuously to the tablet rims while the substrate
rotated. The wet weight gain of applied solution was approximately
8.7 mg, which yielded a dry weight gain of approximately 0.44 mg
HPMC. The tablet was then inverted and the same solution was
applied to the opposing rim in a similar manner. The tablet was
then permitted to dry at room temperature for 24 hours.
[0162] This procedure was independently repeated on 14 additional
tablets.
Example 3
Application of HPMC Surface Treatment Solution to Substrate
Bellyband
[0163] The procedure set forth in Example 2 was independently
repeated on 10 tablets, but with treatment of the belly band as
opposed to the rim of each tablet.
Example 4
Application of HPMC Surface Treatment Solution to Substrate
Faces
[0164] The procedure set forth in Example 2 was independently
repeated on 10 tablets, but with treatment of both opposing faces
as opposed to the rim of each tablet.
Example 5
Comparative Friability
[0165] The treated tablets prepared in accordance with Examples
2-4, along with one control group of 10 tablets that had about 15
.mu.g of deionized water applied to each of their opposing faces,
and a second control group of 10 tablets which were entirely
untreated, were tested for friability using the rotating drop
method of United States Pharmacopeia Chapter <1216> (1995).
The results are shown in Table B below:
3TABLE B Friability Comparison Using USP Chapter <1216>
Tablets (round, flat-faced, beveled edge) 770 mg, hardness
Treatment Treatment Friability value (n = 5) Solution Surface
Friability Factor* 2.57 kp/cm.sup.2 Water both faces 3.75% 2.2 5%
HPMC both faces (Ex. 0.46% 18 4) 5% HPMC Bellyband (Ex. 1.72% 4.8
3) 5% HPMC Rim (Ex. 2) 0.16% 51.8 Control none 8.28% 1 (10 tablets)
*Friability Factor is defined as (friability of the control,
uncoated substrate)/(friability of the coated substrate).
[0166] This Example demonstrated that treating a soft substrate
with the composition of the present invention at predominantly only
the rim of the substrate surface substantially improved the
friability of the treated tablets. In particular, this Example
showed that the friability of tablets, which were treated only
along the rim, was significantly lower that that of the tablets
which were treated on both faces.
Example 6
Preparation of an N-Tack Starch Surface Treatment Solution
[0167] A surface treatment solution having the components set forth
below was prepared as follows:
4 Coating solution ingredients: Deionized water 100 mL N-Tack
Starch* 25.0 g *N-Tack Starch available from National Starch &
Chemical Company.
[0168] 70 mL of deionized water was placed into a beaker and heated
to 70.degree. C. on a hot plate. Then 25.0 grams of N-Tack corn
syrup solids were added thereto, with stirring until all of the
corn syrup solids were dissolved. The resulting solution was
diluted to volume with deionized water at room temperature in a 100
mL volumetric flask.
Example 7
Determination of Treatment Surface Size
[0169] The polymeric dispersion of Example 1 was applied to 15
untreated tablets of Example 2 ({fraction (15/32)}" diameter, 5.56
mm height) in accordance with the procedure set forth in Examples
2-4. For each tablet, the polymeric dispersion (6.7 .mu.g per
mm.sup.2 of surface treated) was applied to one of the treatment
surfaces identified in FIG. 7A through FIG. 7E. The treated surface
area, which was expressed in terms of the percentage of total
substrate surface area that was treated with the polymeric
dispersion, was measured. This procedure is repeated for the
tablets having a 1/4" diameter and a 3/4" diameter, respectively.
Table C below shows the measured results for the treated
tablets:
5TABLE C Treated Surface Area in terms of Total Tablet Surface Area
Tablet w/1/4" Tablet w/{fraction (15/32)}" diameter, diameter,
Tablet w/3/4" 2.8 mm 5.56 mm diameter, 9 mm Treatment Surface
height height height Both faces (FIG. 7A) 86.6% 66.2% 61.4% Belly
Band and both 76.4% 64.2% 60.0% rims* (FIG. 7B) Both faces, 1/2
upper 52.3% 51.7% 50.4% rim and 1/2 lower rim (FIG. 7C) Bellyband,
1/2 upper 47.7% 48.3% 49.6% rim and 1/2 lower rim (FIG. 7D) Both
rims (FIG. 7E) 63.0% 30.4% 21.4% *Overlap area was 1 mm
[0170] This example shows that the percentage of coating varies
depending upon the coating location and the dimensions of the
tablet; however in general, the treated coating surface ranges,
from about 10% to about 90% of the total exterior substrate surface
area.
Example 8
Friability Factor of Substrates
[0171] A. Preparation of Chewable Tablets
[0172] Ibuprofen particles coated with a mixture of
hydroxyethylcellulose and hydroxypropylmethylcellulose, according
to the method disclosed in U.S. Pat. No. 5,320,855 were blended
with aspartame, prosweet powder, citric acid, granular mannitol,
microcrystalline cellulose, flavor and color in a plastic bag by
inverting about 100 times. After magnesium stearate was added
thereto, the mixture was further blended by inverting about 20
times. The components of the resulting blend are set forth in Table
C below:
6TABLE C Components of Chewable Blend Amount Used Component Name
(mg/tablet) Encapsulated Ibuprofen 131.14 (76.25%) Aspartame**
10.82 Prosweet Powder No. 694* 2.54 Citric Acid** 4.26 Mannitol**
528.10 Microcrystalline cellulose*** 84.10 FD&C Yellow No. 6
Aluminum 1.76 Lake Orange flavor** 1.76 Magnesium stearate** 5.52
TOTAL 770 *available from the Virginia Dare Company of Brooklyn,
NY. **These components are readily available and may be
commercially purchased from any of the suppliers set forth in the
"Handbook of Pharmaceutical Excipients (2.sup.nd Ed. 1994).
***available from FMC Corporation under the tradename, "AVICEL
PH101;"
[0173] The resulting blend was then compressed on a rotary tablet
press at 40 rpm using {fraction (15/32)}" diameter flat faced
beveled edge tablet tooling to yield tablets having an average
tablet weight of 770 mg. Compression force was adjusted to yield
final tablets possessing a hardness value of 7.92 kp/cm.sup.2.
[0174] This procedure was repeated to with lower compression force
to yield 10 additional tablets having a hardness value of 5.89
kp/cm.sup.2 and 10 additional tablets having a hardness value of
2.57 kp/cm.sup.2.
[0175] 10 of the tablets having a hardness value of 7.92
kp/cm.sup.2 were then treated with a 5% HPMC polymeric dispersion
produced in Example 1 at both faces in accordance with the
procedure set forth in Example 4 above. Similarly, additional
tablets were independently treated in accordance with the
procedures set forth in Examples 2-4 and the various treatments
solutions and treatment surface criteria set forth in Table D
below:
7TABLE D Friability of Substrates Tablets (round, flat-faced,
Treatment beveled edge) Solution Friability 770 mg, hardness (# of
tablets Treatment Friability Factor** value (n = 5) treated)***
Surface (%) (vs. control) 7.92 kp/cm.sup.2 5% HPMC (10) both faces
0.01 124 4% HPMC (10) both faces 0.34 3.65 3% HPMC (10) both faces
0.43 2.88 Control* (10) none 1.24 1.00 5.89 kp/cm.sup.2 Water (10)
both faces 2.37 1.13 5% HPMC (10) both faces 0.12 22.3 4% HPMC (10)
both faces 0.43 6.23 3% HPMC (10) both faces 1.28 2.09 5% HPMC (10)
bellyband 0.56 4.79 5% HPMC (10) rim 0.10 26.8 Control* (10) none
2.68 1.00 2.57 kp/cm.sup.2 Water (10) both faces 3.75 5% HPMC (10)
both faces 0.46 18.0 4% HPMC (10) both faces 0.37 22.4 3% HPMC (10)
both faces 1.96 4.22 5% HPMC (10) bellyband 1.72 4.81 5% HPMC (10)
rim 0.16 51.8 4% both faces 3.77 2.20 Maltodextrin (10) 2% Pullulan
both faces 2.06 4.02 (10) 4% Pullulan both faces 0.57 14.5 (10) 4%
Pullulan whole 0.78 10.6 (10) tablet 4% N-Tack .RTM. both faces
2.67 3.10 (10) 10% N-Tack .RTM. both faces 0.73 11.3 (10) 25%
N-Tack .RTM. both faces 0.26 31.8 (10) 4% Gelatin both faces 0.63
13.1 (10) Control* (10) none 8.28 1.00 *Friability of control is
average friability of ten (10) uncoated tablets **Friability Factor
is defined as (friability of the control, uncoated
substrate)/(friability of the coated substrate). ***The N-Tack
.RTM. - containing dispersion was produced in accordance with the
procedure set forth in Example 6, but with varying the amount of
the N-Tack .RTM.. The pullulan, gelatin, and maltodextrin
dispersions were independently prepared in accordance with the
procedure set forth in Example 1, but with the substitution of
pullulan, gelatin, and maltodextrin, respectively, for the HPMC,
and with variation of the amount of the polymer.
[0176] This Example showed that the friability of the treated
substrates was significantly reduced by applying the polymeric
dispersion to only a portion of the substrate surface. The
effectiveness of the treatment depends on the water dispersible
polymer employed, the substrate hardness, and the location of
treatment surface. For example, the largest friability factors
(most reduction in friability) were obtained by applying a 5% HPMC
dispersion to both faces of the hardest tablet, and by applying a
25% corn syrup solids dispersion to both faces of the softest
tablet.
* * * * *