Note: Descriptions are shown in the official language in which they were submitted.
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ADHESIVELY BONDED DOSAGE FORM
FIELD OF THE INVENTION
The invention is concerned with solid pharmaceutical dosage
forms that comprise aggregations of preformed subunits that are
adhesively joined together.
BACKGROUND OF THE INVENTION
It is well known to provide dosage forms such as tablets or
capsules for handling pre-measured quantities of materials that
allow consumers to use various materials without the need to use
expensive and cumbersome measuring devices. One reason for the
~
current invention is*to allow for flexible dosing of one or more
drugs.
Japanese unexamined Patent Application Publication H6-9375 by
Ito et al (herein, "Ito") discloses tablets that consist of
smaller "unit tablets" ("subunits," or "tablet subunits," or
"capsule subunits" herein) which are connected by a "cement"
that acts as an adhesive. The connecting part is explicitly
stated in those cases to be the cement, which is alleged to be
breakable while leaving the unit tablets intact. Leaving
aside the practicality of breaking through, either
mechanically or by dissolving, said cement connecting part,
the application discloses production of smaller tablet
structure tablets each comprising intact unit tablets. The
application fails to disclose tablet subunits that are not
"unit tablets." In addition, the application is specific in
the mode of manufacture of said tablets that it discloses.
Said mode of manufacture consists of apposing ("mating") the
unit tablets to be joined and then forming a "connecting part"
with cement. Said application does not disclose producing
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said tablets by applying adhesive to an inert subunit that is
not simultaneously apposed to or adjacent to another subunit.
In addition, because Ito states that the subunits of said
application are "unit tablets," it would not be contemplated
to create a score in a unit tablet that is in general use to
facilitate tablet breaking. Further, a marking on a tablet,
such as a printed mark, that may also facilitate tablet
breaking such as by delineating a bisecting part of a tablet
subunit, would similarly not be implied by Ito's application.
The current invention utilizes the term "separation mark" or
"separation marking" to indicate a score, a printed mark, or
similar addition to a tablet subunit that may guide or
facilitate tablet breaking.
The current invention most clearly differs from Ito's
disclosures and the implications of his disclosures in that
said application contemplates either that dosage forms of his
invention are ingested whole or else are broken or divided
only through the "cement" with the tablet subunits considered
"building blocks" a la indivisible atoms that form a molecule.
In contrast, the current invention discloses dosage forms that
are adapted to being broken through a tablet subunit part of
said dosage forms. Therefore the methods of breaking said
dosage forms of the invention involve breaking through a
tablet subunit and not through an adhesive (cement).
The current invention utilizes the general term "inert" to
describe a tablet subunit that lacks any active pharmaceutical
ingredient (i.e., a"drug"). "Inert" is intended to include
tablet subunits that either lack any controlled-release
function or that have a controlled release function. The term
"inactive" is utilized to indicate a tablet subunit that lacks
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any active pharmaceutical ingredient and that also lacks any
immediate release function. Therefore, any inactive tablet
subunit is also considered inert, but an inert tablet subunit
may or may not be inactive.
SUMMARY OF THE INVENTION
The present invention is concerned with novel dosage forms and
methods of their manufacture, plus methods of breaking said
dosage forms and administration of a broken part of said dosage
form.
The invention provides a solid pharmaceutical dosage form
comprising a plurality of adhesively-joined subunits. Said
dosage form contains at least one or more of the following:
A. (i) a first inert tablet subunit and (ii) a second
active subunit;
B. (i) a first tablet subunit with a pharmacologically
inactive layer in which said layer has a mass of at least 20
mg and (ii) a second subunit;
C. a separation mark on a tablet subunit; or
D. (i) a first tablet subunit and (ii) a second capsule
subunit.
The dosage forms consist of a suitable adhesive substance
interposed between and joining (or, "connecti.ng," or "bonding,")
a plurality of preformed subunits, preferably tablets but
possibly involving one or more capsule subunits. The invention
differs from the Ito disclosure in that the current invention
involves at least one of the following novel aspects:
A. In a preferred embodiment, dosage forms containing at
least one tablet subunit with an active drug ("active subunit")
and at least one tablet subunit made of only pharmaceutically
inactive material ("inert tablet subunit") are disclosed herein,
whereas Ito only discloses an exemplary placebo tablet made only
of inactive subunits;
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B. In another' preferred embodiment, dosage forms contain
two or more active subunits adhesively joined together where at
least one of the active subunits has a separation mark that is
preferably a score;
C. In another preferred embodiment, dosage forms have two
or more active subunits adhesively joined to one or more inert
tablet and in said embodiment, a separation mark such as a score
is optional;
D. In another embodiment, a capsule subunit may be
adhesively joined to a tablet subunit; or
E. In another preferred embodiment, the invention involves
a dosage form comprising a plurality of active subunits each
adjoining an inert subunit that may be readily breakable without
damaging any active subunit.
An inactive tablet subunit of a dosage form of the invention is
preferably adapted to be broken, such as a tablet subunit that
is provided with a separation mark which may be a score; such a
subunit may optionally be an active or an inactive subunit. An
active tablet subunit may also be adapted to be conveniently
breakable and may be provided with a separation mark such as a
score.
An active subunit herein contains a pharmacologically effective
quantity of a drug or drugs. The terms "drug," "active drug,"
"active pharmaceutical ingredient" or "active ingredient,"
"active pharmaceutical compound" and the like herein include not
only pharmaceuticals such as those that in the United States are
regulated by the Food and Drug Administration, but also includes
vitamins and minerals.
In many cases, an inert subunit will link two discrete active
subunits. The term "inert tablet subunit" as used herein means
a structural unit made on a tabletting apparatus wherein the
structural unit contains pharmaceutically acceptable materials,
e.g. excipients, diluents, fillers etc. which have no detectable
pharmacological effects at the amounts used in the dosage form.
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When the term "inactive subunit" is used, it is used to describe
a subunit which has no detectable pharmacological effects and
has no controlled release function.
The invention provides a method of accurately providing a
predetermined part of a dosage form for administration as well
as providing a whole dosage form. Preferably but not always,
breaking a subunit of the invention will not involve breaking,
damaging, dissolving, etc. the adhesive bond between subunits.
The invention contemplates that one usage of a dosage form may
involve breaking through two or more subunits that also involves
breaking through a discrete portion of the adhesive bond that
joins them.
The invention also includes a method of administering a part
of an active subunit of a solid pharmaceutical dosage form by
breaking said pharmaceutical dosage form through an active
subunit to obtain a part comprising an active subunit and then
orally administering the part having the active subunit to a
patient in need thereof.
A further embodiment is directed to a method of administering
one active subunit of a dosage form having at least two active
subunits adhesively joined to an inert tablet subunit by first
breaking said inert tablet subunit to form two parts each of
which comprises an active subunit and a part of said broken
inert subunit and thereafter administering one of said parts
to a patient or other appropriate host. The dosage forms and
parts formed by breaking are intended to be given enterally,
such as orally. Other means of administration, such as
through a naso-gastric tube or gastrostomy tube or per rectum,
are contemplated as well.
The invention contemplates crushing a part of a whole dosage
form that has been formed by breaking per the methods of the
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invention, so that administration through a feeding tube and
the like may be conveniently accomplished.
The invention further includes a method of making a solid
pharmaceutical dosage form by:
(a) first, applying adhesive to a first active or first
inert subunit; and
(b) second, bringing said first active or inert subunit
containing adhesive into contact with a second active or inert
tablet subunit (that optionally may have adhesive applied as
well) and optionally applying pressure to the subunits.
It will be appreciated that no limitation is placed upon the
nature, contents, active or inactive ingredients, or size or
shape of either the subunits or the final dosage form, except
that the final dosage form should be safe to use and is most
preferably able to be taken into the body (e.g., ingested) by
its intended user.
The invention utilizes substance(s) with sufficient adhesive
ability to allow the subunits to adhere to one another to form
one cohesive dosage form. For commercial use, preferably said
dosage forms will remain intact through the manufacturing and
transport phases until it reaches a patient, nurse, pharmacist,
etc. These novel dosage forms have many embodiments and may
comprise many different arrangements, many different shapes,
types of active ingredient(s), types of inactive ingredient(s),
number of subunits, etc. without any limitation. Examples
representing embodiments of the invention are given herein to
exemplify but not to limit the number of useful possibilities
that are within the scope of the invention.
Accordingly it is a primary object of the invention to provide a
novel pharmaceutical dosage form which contains one or more
active or inactive ingredient(s) in more than one separately-
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produced active subunit which is adhesively bonded onto an inert
linker subunit wherein said dosage form may be separated into
two or more parts by breaking said dosage unit at a location or
locations within the active subunit to provide a predetermined
amount of a drug or drugs contained in said dosage form.
It is also an object of the invention to provide a novel
pharmaceutical dosage form which contains one or more active or
inactive ingredient(s) in more than one separately-produced
active subunit which is adhesively bonded onto an inert subunit
wherein said dosage form may be separated into two or more parts
by breaking said dosage unit at a location or locations within
the inert subunit to provide a predetermined amount of a drug or
drugs contained in said dosage form.
It is also an object of the invention to provide a novel
pharmaceutical dosage form which contains one or more active or
inactive ingredient(s) in more than one separately-produced
active subunit which is adhesively bonded onto an inert linker
subunit wherein said dosage form may be separated into two or
more parts by breaking said dosage unit at locations within one
or more of the active subunits and within the inert linker
subunit to provide a predetermined amount of a drug or drugs
contained in said dosage form.
These and other objects of the invention will become apparent
from the present specification.
A"subunit" is a preformed structure classified herein as
either as an active subunit, a capsule subunit, or inert
tablet subunit or an inactive tablet subunit. Materials such
as adhesive substance(s) or film such as hydroxypropyl
methylcellulose that may be used to coat a subunit, are not
themselves considered subunits.
"Preformed" refers to separate production of a subunit. A
tablet subunit of a dosage form of the invention is produced
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as a tablet, and becomes a subunit when it is part of the
dosage form of the invention. Similar considerations apply to
a capsule subunit of the invention.
Tablet subunits of the invention may be layered structures as
are well known. The invention may encompass a
pharmacologically inactive layer of a tablet comprising a
plurality of layers to serve as a breaking point and thus said
pharmacologically inactive layer may serve a similar function
in the invention as does an inert tablet subunit. Preferably
said inactive layer has a mass of at least 20 mg and more
preferably 50-900mg; or 150mg-750mg or 400-600mg; a volume of
at least 10 cubic mm and more preferably 25 cubic mm; and/or a
length along the longest axis of the dosage form of at least 1
mm, and more preferably 2 mm. Thus said inactive layer may
play a role in dosage form subdivision by serving as a
breaking region.
"Tablet" and "capsule" are defined in their usual ways.
Active subunits may contain one or more drugs.
"Pharmaceutical dosage form" herein refers to a solid dosage
form containing two or more subunits adhesively bonded
together. The preferred solid dosage form is an oral dosage
form.
BRIEF DESCRIPTION OF THE DRAWINGS
All drawings depict dosage forms of the invention in which
contiguous subunits are adhesively joined. All views are
external views.
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Fig. 1 is a drawing of a top view of the dosage form of the
invention depicting three subunits.
Fig. 2 is a schematic top view of a dime-shaped dosage form
that has three subunits, one of which is scored.
Fig. 3 is a schematic top view depicting four active subunits
each joined by an adhesive substance to an inert tablet
subunit.
Fig. 4 depicts five tablet subunits, two of which each
adhesively join three other subunits.
Fig. 5 is a schematic top view that depicts a dosage form of
the present invention in the shape of a capsule. The inert
tablet subunit has two indentations that each contain a
preformed active subunits.
Fig. 6 is a schematic side view depicting a dosage form
consisting of three scored, adhesively joined active tablet
subunits.
Fig. 7 is a schematic side view depicting a dosage form
consisting of three active tablet subunits each of which is
adhesively joined to two inert tablet subunits.
Fig. 8 is a schematic top view of a three-subunit dosage form.
Fig. 9 is a schematic top view of a four-active subunit dosage
form in which the four active subunits are adhesively bonded
together.
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Fig. 10 depicts a side view of a dosage form containing four
tablet subunits.
Fig. 11 depicts a dosage form with five subunits.
Fig. 12 depicts a dosage form with three subunits joined
together adhesively.
Fig. 13 depicts a dosage form with three tablet subunits, none
of which are scored.
Fig. 14 depicts a dosage form with three subunits, one of
which is scored.
Fig. 15 is an exploded depiction of a two-subunit dosage form,
one of which is a trilayer tablet subunit.
Fig. 16 is a partially exploded perspective view of a dosage
form having two active subunits, one of which is a tablet
subunit and one of which is a capsule subunit, and an inert
tablet subunit.
Fig. 17 is a perspective view of a partially exploded dosage
form having four active subunits and an inert tablet subunit
adjoining said active subunits.
Fig. 18 is a perspective view of a partially exploded dosage
form having two active subunits and an inert tablet subunit
with score marks placed in the inert tablet subunit.
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DETAILED DESCRIPTION OF THE INVENTION
The invention contemplates that an active subunit comprise a
drug or drugs, that a capsule subunit is an active subunit
(excepting placebo formulations for clinical trials and the
like), and that inert tablet subunits lack a drug.
The dosage forms of the invention may be made by joining
individual tablets orcapsules which are shaped in any desired
configuration by such means as the use of tablet punches and
dies (tablets), or encapsulating equipment (capsules). Said
methods of manufacture are not limiting. The method of
joining involves material(s) with adhesive properties. There
may be additionally be materials with non-adhesive
characteristics between the subunits.
The dosage forms may comprise active subunits and inert tablet
subunits having a plurality of various cross-sectional shapes,
including without limitation round tablets, half-round,
quarter-round, oval, trapezoidal, triangular, rectangular,
etc., that are be adhesively bonded to each other. In a
preferred embodiment of the invention, the active subunits
and/or capsule subunits may be separated from each other in a
convenient manner by an end-user, nurse, pharmacist, etc.
without damaging the function of said subunits. It is
preferred that such non-damaging separation of at least one
active subunit (with or without a potion of the inert tablet
subunit) from the dosage form will be able to be performed
manually; however, there may be cases in which manual
separation is inconvenient or not possible without damaging
one or more subunits. In such cases, it is within the scope
of the invention that convenient mechanical means of
separation of at least one subunit from the entire dosage form
may exist, utilizing such implements as a commercially-
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available tablet cutter, kitchen knife, etc. It is also
within the scope of the invention that because the invention
contemplates dosage forms comprising subunits with a variety
of shapes, with some dosage forms containing more than two
subunits, it may not be convenient to use a standard tablet
cutter, and it may therefore be desirable to create a tablet
cutter specifically adapted for the specific dosage form to
optimize ease of non-damaging subunit separation.
By use of the procedures of the invention, pharmaceutical
dosage forms containing two or more separate subunits may be
made.
In general, an effective amount of an adhesive is used to join
any two surfaces together. No limitation is intended as to
the amount of adhesive needed. The amount of adhesive needed
is dependent on multiple factors, such as the size and density
of the dosage form.. In general, a minimum amount of adhesive
is preferable. Generally, the amount of adhesive may comprise
from 0.1 to 5 mils of adhesive spread over an area of
approximately 0.5 to 100 sq mm., more or less, depending on
the particular tablet size and area and number of the surfaces
being joined together. In the case of veterinary dosage forms,
such areas may be increased significantly.
Fig. 1 is a schematic side view of the invention that depicts
two active subunits, 52 and 54, respectively, joined by inert
tablet subunit 56. Adhesive joins active subunit 52 to one
side of the inert tablet subunit 56 and also joins active
subunit 54 to the other side of the inert tablet subunit 56.
Active subunits 52 and 54 are conveniently separable from each
other by, for example, cutting through the inert tablet
subunit 56, or by grasping active subunits 52 and 54 and
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applying force centered on the inert tablet subunit 56,
including rotary force or perpendicular force. Active
subunits 52 and 54 are substantially identical.
The figures are not necessarily drawn to scale and are not
intended to limit the size or shape of the dosage form or any
subunit. Inert tablet subunits such as subunit 56 in Fig.
generally may have a mass greater than 20mg or more preferably
form 50mg to 900mg, or even more preferably from 150-600mg or
even more preferably form 400-500mg. The length and thickness
will be selected ensure that the dosage form may be enterally
administrable while being sufficiently robust to avoid undue
amounts of breakage during packing, shipping and handling.
As shown in Fig. 2, a dosage form that is circular (coin-
shaped such as dime-shaped) is shown on top view having active
tablet subunits 62 and 6, that are each joined to a scored
inert tablet subunit 66 with score 68. Inert tablet subunit
66 may be conveniently manually or mechanically broken without
damaging either active subunit 62 or active subunit 64.
Optionally a dosage form of this form could have one or both
active tablets scored as well.
Figure 3 depicts four active subunits, 72, 74, 76 and 78
joined via an adhesive substance to an inert tablet subunit
element 79 that if broken can provide one or more subunits to
be ingested.
Figure 4 is a drawing which shows three active subunits, 80,
82 and 84, none of which are connected to each other, but all
of which are connected to inert tablet subunits 85 and 86 on
opposite ends of the active subunits. Breaking the dosage form
through the inert subunits may be accomplished without
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damaging any active subunit. Not shown is a similar design in
which the active subunits are attached only on one end to an
inert tablet subunit. , In practice, the gaps 87 and 89,
between the active subunits, may be smaller than shown.
Figure 4 does not exclude the possibility that the active
subunits so arranged may actually touch.
Figure 5 is a drawing of a dosage form comprising three
subunits. Active subunits 92 and 94 are adhesively bonded to
indentations (depressions) 92A and 94A which are formed in
subunit 90. Subunit 90 could be a active subunit containing an
active ingredient(s) or subunit 90 could also be an inert
tablet subunit. Dosage forms similar to Fig.5 may be made in a
variety of shapes with varying shaped indentations or
depressions. The entire dosage form is ingestible. The dosage
form may be broken at score 96 to separate the active subunits
in the dosage form into two parts.
As shown in Fig. 6, a dosage form of the invention may
comprise a stacked multilayer arrangement of substantially
flat active subunits 8, 10 and 12 that contain, respectively,
score marks 5, 7, and 9 and which are adhesively bonded
together with small quantities of adhesive 6 to form a layered
structure.
Fig. 7 shows a dosage form in which three active subunits, 14,
16, and 18 are held together with inert tablet subunits 20 and
22 that are adhesively joined to a side of each of the active
subunits. While Fig. 7 shows two inert tablet subunits on the
side of the tablets, it is possible to use only one, two, or a
plurality of inert tablet subunits that may be positioned to
form a stable and useful dosage form.
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Fig. 8 depicts a top view of a dosage form having an inert
tablet subunit 34 that joins ends 36 and 38 which contain
active ingredients. Lines 40 and 42 represent the adhesively
joined edges of the active subunits. If desired, it is
convenient to break through the inert tablet subunit without
affecting either active subunit.
Fig. 9 shows a top view of a four-active subunit dosage form
that is made by adhesively bonding together segments 24, 26,
28 and 30, which each contribute 90 of arc to the final shape
of the dosage form. This dosage form is particularly useful
when it is desirable to simultaneously administer several
different active drugs. Score 27 approximately bisects
subunit 30 and score 29 approximately bisects subunit 26. The
dosage form is therefore conveniently divisible through both
scores,that form a continuous linear indentation across the
dosage form. Adhesive 6 that is the same type of adhesive
used in Fig. 6 joins the subunits together.
Fig. 10 shows a drawing of a three-active subunit dosage form
in which an outer active subunit 100 is bonded with adhesive
layer 101 to a middle active subunit 102. Outer subunit 104 is
bonded with adhesive to inert tablet subunit 103, which is
adhesively bonded to middle active subunit 102.
Fig. 11 shows a drawing of a three-active subunit dosage form
in which the outer active subunits 105 and 109 are each
adhesively bonded to inert tablet subunits 106 and 108,
respectively, said inert tablet subunits being adhesively
bonded to middle active subunit 107.
Fig. 12 shows a drawing of a three-active subunit dosage form
in which active subunit 110 is bonded with adhesive 111 to
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middle active subunit 112. Active subunit 114 is bonded with
adhesive 113 to middle active subunit 112.
Fig. 13 shows inert tablet subunit 116 adhesively bonded to
active subunits 115 and 115A. The active subunits contain the
same drug. The dosage form may be broken conveniently between
subunits 115 and 115A through subunit 116.
Fig. 14 depicts inert tablet subunit 118 with a score that is
between different active subunits 120 and 120A, facilitating
tablet breaking when desired.
Fig. 15 depicts in an external view a dosage form consisting
of two tablet subunits adhesively joined together at interface
308 that comprises an adhesive substance. The tablet subunit
that consists of layers 300, 302 and 304 is produced,
separately on a tri-layer tablet press. The vertical lines in
between layers 300 and 302, and between layers 302 and 304,
represent the interfaces between the layers that are all of
different colors. Layer 300 contains a therapedtic quantity
of amlodipine besylate (amlodipine) and layer 304 contains a
therapeutic quantity of chlorthalidone. Layer 302 is formed
from an inactive granulation and, due to mixing between layers
in the tablet-forming process, contains pharmacologically
ineffective quantities of both amlodipine and chlorthalidone.
Said trilayer tablet that is a subunit of the dosage form
depicted in Fig. 15 is produced first by allowing' a
granulation containing amlodipine and suitable excipients into
the die, then tamping; then allowing a granulation lacking an
active ingredient into the die, then tamping, then allowing a
granulation containing amlodipine into the die, then pre-
compressing and then fully compressing to form a coherent
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tablet. The upper punch is beveled and the lower punch is
flat-faced.
Tablet subunit 306 contains benazepril and is produced
separately in a conventional fashion. Subunit 306 is
adhesively joined to the tri-layer tablet described above with
shellac.
An advantage of the dosage form depicted in Fig. 15 is that a
tri-layer tablet such as is described above (layers 300,302
and 304) may be used to produce the more complex, three-active
drug, dosage form of Fig. 15 while retaining the ability to
break the dosage form through layer 302 and producing two
useful dosage forms. One dosage form would contain a
therapeutic quantity of amlodipine only and the other would
only contain therapeutic quantities of chlorthalidone and
benazepril only.
Numerous other variants of the design of the dosage form
depicted in Fig. 15 may be utilized within the present
invention.
Fig. 16 is a partially exploded perspective view of a dosage
form that consists of part 203 adhesively joined to subunit
208. Subunit 200 in this example is a capsule subunit. Part
203 contains subunit 200 and inert tablet subunit 204.
The length of subunit 204 relative to the other subunits makes
it relatively easy to break through.
Fig. 17 depicts an external view of a dosage form that
contains four active tablet subunits that are all adhesively
joined to linker tablet subunit 218 that is inactive.
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Subunits 210, 212, 214, and 216 are all active. In the
current example, each of said active subunits contains a
therapeutically effective quantity of a different drug. In
alternative embodiments, two or more active subunits may
contain the identical drug.
Note that tablet subunit 214a is shown in its proper position
in the dosage form of Fig. 17 and also is shown in a phantom
exploded view as 214b.
Fig. 18 depicts a partially exploded external view of a dosage
form containing part 234 comprising a double-scored inactive
tablet subunit 227, interface 230, tablet subunit 232, and
shellac layer 224; and tablet subunit 220. Top score 226 and
bottom score 228 are created manually with a file.
Scores 226 and 228 adapt tablet subunit 227 to be broken more
easily than if no scores were present. Optionally, subunit
227 could have been a scored active tablet subunit.
The tablet subunits that are adhesively bonded together may be
made using such techniques as are employed in the
pharmaceutical industry to produce conventional tablets. These
techniques include, without limitation, wet granulation
methods; dry granulation techniques, such as slugging and
grinding; or direct compression powder blends.
PHARMACEUTICAL USES
Generally, many useful solid dosage forms may be usefully
produced by the methods of the invention. There are several
practical advantages to the invention. These include, without
limitation:
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A. There will no longer be a need to co-formulate
different products when desiring to combine them into one
dosage form. Not only will the methods of the invention save
time and money in such development, but such savings will make
it easier to initiate testing of combination therapies. The
vexing issue of incompatibilities between different
formulations will cease to be limiting. Several other
physical and chemical considerations will no longer be
limiting as well.
B. Two or more doses of the same drug product may be
produced separately, then joined as tablet subunits or capsule
subunits. If accurately separable from each other, more
precise dosing will then be available than is currently
achievable with conventional scored tablets. Regarding
joining two capsules, there is currently no marketed product
in the United States that provides the ability to separate a
capsule dosage form into two capsule subunits.
C. The invention allows a tablet and a capsule to be
joined together in one dosage form, which advances the
pharmaceutical art in a novel and potentially important way.
D. Physician and patient acceptance of combination
therapies, as well as acceptance by academics, government,
regulatory bodies, and society at large may be enhanced by
allowing flexibility in dosing of combination products by
following the methods of the invention.
E. The invention is well-suited for formulating
combination drug products, i.e. dosage forms which contain two
more active ingredients. When the dosage forms of the
invention comprise more than one active drug, the dosage forms
of the invention may provide a convenient manner of improving
patient compliance with dosing regimens while at the same time
minimizing formulation problems. These benefits are in
addition to the advantage of being able to discontinue therapy
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with one or more drugs by removal of one or more subunits
containing a particular drug from the dosage form. A further
benefit is the simplification of the prescribing and
dispensing of multiple individual drug products.
F. Patients allergic to one member of a combination
product can break some preferred embodiments of the invention
and ingest one drug of the combination tablet, something not
able to be safely done currently.
The invention provides a method of making a dosage form of a
combination of different drugs where the different drugs may
be separated from the combiriation without any trace amount of
another drug being present in combination with another drug.
For example, when multilayer tablets are formed on a
multilayer tablet press, it is difficult or nearly impossible
to exclude all traces of the granulation for one layer from
appearing in a compressed layer of a another granulation due
to air currents and vibration which cause the granulations to
disperse or form aerosol like dispersions in the area where
the granulations are fed into the dies on the multilayer
press. The present invention allows the separate components of
the combination dosage form to be separately tabletted and
adhesively joined in such a manner that there is no cross-
migration of the individual drugs between the separate active
units in a dosage form according to the present invention.
Thus when the active subunits are obtained apart from the
dosage form of the invention, there is no cross-contamination
of the individual drugs. This is particular important when
patients are allergic to a particular drug.
As mentioned above, the invention contemplates that solid
dosage forms may generally benefit from the invention's
teachings. What follows are some specific examples of
products that either may be combined together
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Some useful combinations of drugs are, with examples in
parentheses:
Combinations of anti-anginal agents. These include any
combination of the following drug classes:
A. Calcium channel blocking agents (amlodipine salt,
diltiazem, lercanidipine)
B. Beta-blocker (atenolol, metoprolol, propranolol)
C. Organic nitrate preparation (isosorbide mononitrate
or dinitrate);
Combination of anti-anginal agent (see above) with anti-
platelet agent, such as aspirin or clopidogrel;
Combination of any two hypoglycemic agents;
Combination of potassium salt (preferably KC1) and any
thiazide-type or loop diuretic;
Combination of hypolipidemic agent with any of a variety of
representatives of drug classes: hypoglycemic agent, anti-
platelet agent, anti-anginal agent, organic nitrate,
antihypertensive agent:
Hypolipidemic agent may be a:
Statin (si.mvastatin, atorvastatin with or without torcetrarib,
rosuvastatin, lovastatin, rosuvastatin, fluvastatin), a
fibrate (fenofibrate, gemfibrozil, bezafibrate, ciprofibrate,
clofibrate), or member of other classes (niacin, ezetimide,
acipimox)
Hypoglycemic agents:
Thiazolidinediones: Pioglitazone, rosiglitazone
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Sulfonylureas: Glyburide, glipizide, glimepiride,
chlorpropamide
Biguanides: Metformin
Meglitinides: Nateglinide, repaglinide
Glucosidase inhibitors: Acarbose, miglitol;
A member from two or more of the following three classes:
A. Diuretic (HCTZ, furosemide)
B. Digoxin (and other cardiac glycosides)
C. Beta-blocker approved for congestive heart failure
treatment (metoprolol, carvedilol);
Combinations of two or more antihypertensive agents, most
preferably one member from different classes as described
below:
Beta-blockers:
Acebutolol, atenolol, bisoprolol, celiprolol, metoprolol,
mebivolol, carvedilol (a mixed alpha-beta blocker), nadolol,
oxprenolol, penbutolol, pindolol, propranolol, timolol,
betaxolol, carteolol,
Calcium antagonists (calcium-channel blockers):
Nifedipine, amlodipine, verapamil, diltiazem, nisoldipine,
felodipine, isradipine, lacidipine, lercanidipine,
nicardipine, manidipine
Thiazide-type diuretics (with or without potassium-retaining
diuretics such as triamterene, amiloride, or spironolactone:
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Hydrochlorothiazide, chlorothiazide, cyclopenthiazide,
polythiazide, bendrofluazide, hydroflumethiazide,
chlorthalidone, indapamide, methylclothiazide, metolazone
Angiotensin converting enzyme inhibitors:
Captopril, enalapril, lisinopril, ramipril, trandolapril,
quinapril, perindopril, moexipril, benazepril, fosinopril
Angiotensin receptor blockers:
Losartan, valsartan, candesartan, telmisartan, eprosartan,
irbesartan
High-ceiling (loop) diuretics (with or without potassium-
retaining diuretics such as triamterene, amiloride, or
spironolactone):
Furosemide, torsemide, ethacrynic acid, bumetamide
Aldosterone antagonist diuretics:
Spironolactone, eplerenone
Alpha-blockers:
Doxazosin, terazosin, prazosin, indoramin, labetolol (a mixed
alpha-beta blocker)
Central alpha-agonists:
Clonidine, methyldopa
Imidazoline: Moxonidine
Direct vasodilators:
Hydralazine, minoxidil
Adrenergic neuronal blocker: Guanethidine.
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It will be appreciated that certain combinations, such as a
beta-blocker and a diuretic, are more preferred than others,
such as verapamil and a beta-blocker, or furosemide and
hydrochlorothiazide. The same is true for other combinations.
In addition to the above, many products benefit from accurate
separability, such as into half-doses, quarter-doses, etc.
Some prominent examples that may benefit more than most
include narrow therapeutic index drugs. Examples of these are
warfarin sodium and other coumarins, L-thyroxine, and digoxin.
Other examples especially benefiting from being formulated as
to be accurately separated when desired are vasoactive drugs
such as calcium antagonists and beta-blockers. For example,
many if not all of the drugs listed above regarding
combinations may be usefully formulated per the invention and
could then be the only active drug in a dosage form of the
invention. Thus, a great many single drug products can be
precisely separated one from the other by the invention; also,
a combination drug product can be placed together in a subunit
and thus be precisely separated as a fixed dose combination,
No limitation is intended regarding the number of subunits in
the above or any of the instructive examples provided. No
limitation is intended as to the many examples of useful
combinations of dosage subunits that may benefit from this
invention. Numerous other monoagents, in addition to those
listed above may be formulated alone, or in combination with
other drugs using the procedures of the invention.
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MANUFACTURING
Preferred adhesive substances include, without limitation, the
following:
MFG. Material
Rohm GmbH & Co. KG Methacrylic Acid Copolymer
Type B NF
(Eudragit S 100)
Rohm GmbH & Co. KG Methacrylic Acid Copolymer
Type C NF
(Eudragit L 100-55)
Rohm GmbH & Co. KG Methacrylic Acid Copolymer
Type A NF
(Eudragit L 100)
Mantrose-Haeuser Company #4 Pharmaceutical Glaze
(Shellac)
45/200
Mantrose-Haeuser Company #4 Pharmaceutical Glaze
(Shellac)
45/200 with Stabilized Shellac
In addition, suitable adhesive materials may be selected from
the following list:
As synthetic adhesives, one may cite the following specific
examples.
= As thermosetting resin adhesives, the chemical reaction
types of urea resin, melamine resin, phenol resin, epoxy
resin, polyester resin, polyimide resin, and the like.
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= As thermoplastic resin adhesives, the solvent vaporization
types of solvent-type vinyl acetate resin, emulsion-type vinyl
acetate resin, vinyl chloride-vinyl acetate copolymer resin,
nitrocellulose, acryl-vinyl acetate copolymer resin, ethylene-
vinyl acetate copolymer resin, and the like; the chemi'cal
reaction types of cyanoacrylate, anaerobic acrylic resin,
urethane resin, and the like; the cooling (hot-melt) types of
ethylene-vinyl acetate copolymer resin, polyamide, polyester,
and the like; the pressure sensitive type of acrylic resin,
and the like.
= As synthetic rubber adhesives, the solvent-vaporization
types of chloroprene rubber, nitrile rubber, reclaimed rubber,
latex, and the like; the chemical-reaction type of urethane
rubber, and the like; the cooling (hot-melt) type of
polystyrene-polyisoprene-polystyrene block copolymer, and the
like; the pressure-sensitive types of butyl rubber,
polyisobutylene rubber, silicone, and the like.
= As polymer alloy adhesives, the chemical-reaction types of
vinyl-phenolic, rubber-phenolic, epoxy-phenolic, nylon-epoxy,
nitrile-epoxy, and the like.
As natural adhesives, one may cite the following specific
examples.
= The solvent-vaporization types of starch, casein, dextrin,
gum Arabic, and the like; the cooling (hot-melt) types of
asphalt, glue, rosin, and the like; and the pressure-sensitive
types of conjugated polysaccharides, natural rubber, and the
like.
As adhesives, one may cite the following specific examples.~
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= As rubber adhesives, mixtures of tackifiers, softeners,
antioxidants, and the like with elastomer.
= As acrylic adhesives, synthetic products of ester acrylate,
and the like.
= As silicone adhesives, the substances produced from silicone
rubber and silicone resin of the aqueous-emulsion type,
oligomer type, and hot-melt type.
= Otherwise, polyether adhesive, polyurethane adhesive, etc.
Furthermore, it is possible to process these adhesives in tape
and sheet form for use.
As viscous substances producing viscosity by water, one may
cite the following specific examples.
= As polymers possessing carboxylic groups, acrylic acid
copolymers and the like with acrylic acid as the constituent
monomers; and as substances with salt there are monovalent and
bivalent salts and the like of sodium salt, potassium salt,
magnesium salt, and calcium salt.
= As cellulose ethers, carboxymethyl cellulose sodium,
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl
cellulose, crystal cellulose-carboxymethyl cellulose sodium,
and the like.
= As natural viscous substances, mucin, agar, gelatin, pectin,
carrageenin, sodium alginate, locust bean gum, chitin,
chitosan, traganth powder, and the like.
= Polyethylene glycol with a molecular weight of 200,000 or
more, and the like.
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As viscous substances that produce viscosity by organic
solvents such as alcohol and the like, one may cite the
following specific examples.
= Hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
ethyl cellulose, hydroxypropylmethyl cellulose phthalate,
hydroxymethyl cellulose acetate-succinate, acrylic acid
copolymer, shellac, waxes, and the like.
ACTIVE FORMULAS
DIRECT COMPRESSION FORMULAS
The following formulations are used in making single layer
tablets that are subsequently adhesively joined. A Manesty
16 station Beta Press (single layer rotary tablet press) is
used to make the amlodipine and benazepril tablets. The two
formulations are directly compressible powder blends. The
blending both of the amlodipine formulation and the benazepril
formulation is performed in a Patterson-Kelly "V" blender. The
tablets are compressed using '-4, inch flat faced beveled edge
tablet punches to a hardness of 25 kiloponds. The tablet
weight is 62.0 mg for the amlodipine tablet and 54.0 mg for
the benazepril tablet. Weights in mg of the granulation
comprising each segment follow:
Amlodipine Tablet Formula Mg.
Dibasic calcium phosphate anhydrous 51.13
Amlodipine besylate 7.15
Sodium starch glycolate (Explotab ) 2.48
Magnesium stearate 0.93
FD&C Blue #1 Aluminum Lake 0.31
Total 62.00
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Benazepril Tablet Formula Mg.
Lactose 310 monohydrate 42.03
Benazepril HCl 9.00
Crospovidone 2.16
Magnesium stearate 0.54
FD&C Red #40 Aluminum Lake 0.27
Total 54.00
FLUID BED WET GRANULATION FORMULATIONS
The following two formulas are used to manufacture wet
granulations which are subsequently compressed into single
layer tablets and may be adhesively joined together.
The wet granulations are all made using the following fluid
bed granulator procedure.
1. Screen the Active Pharmaceutical Ingredient (API)
(amlodipine or chlorthalidone), Starch 1500, Sodium
Starch Glycolate and Microcrystalline Cellulose
through a US 20 mesh sieve.
2. Screen the Magnesium Stearate through a US 30-mesh sieve.
3. Weigh all of the ingredients. Balance.
4. Prepare 12% Starch slurry by adding the 150g of Starch
1500 to the 1100g of Water while stirring with a
Lightnin mixer with a propeller shaft. Mix for a minimum
of 10 minutes. Mix continuously) during the granulation
procedure.
5. Place the &~ Microcrystalline Cellulose, API, 22.5 g of
Sodium Starch Glycolate, and the remaining
Microcrystalline Cellulose into a Mendel Fluidbed
Dryer/Granulator set up with the 20 liter bowl and a top
spray nozzle. Mix for a minimum of 10 minutes before
starting to spray. Set up parameters are:
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Inlet Temp: 60 to 70 C
Spray Rate: 25 to 35 g/min
Atomization Pressure: 1 bar
6. Spray all of the Starch 1500 slurry on to the blend.
7. Dry the granulation to about 2% moisture.
8. Mill the dried granulation using the Comil with a 20 mesh
equivalent screen.
9. Place the milled granulation into a 4 quart V-Blender and
add the remaining 12.5g of Sodium Starch Glycolate and
mix for 5 minutes.
10. Add the Magnesium Stearate to the V-Blender and mix for 3
minutes.
The tablets are compressed on a Manesty 16 station Beta Press,
single layer rotary tablet press. The tablets are compressed
using 1-4 inch flat faced beveled edge tablet punches to a
hardness of 20-25 kiloponds. The amlodipine tablet weight is
60.0 mg and the chlorthalidone tablet weights 70mg.
The following give formulae for use in producing granulations
that may be used in tablets of the invention.
Ingredient % of Wet % per Amount
Granulation tablet per
tablet
Amlodipine besylate 17.138 16.667 10
Calcium Phosphate, 54.842 53.333 32
anhydrous
Starch 1500 15.424 15.000 9
Avicel PH102 10.282 10.000 6
Sodium Starch 2.314 2.250 1.35
Glycolate
(Intragranular)
Sodium Starch - 2.250 1.35
Glycolate
(Extragranular)
Magnesium Stearate - 0.500 0.3
Water (for 12% As Req'd - -
Starch Slurry)
Total 100% 100% 60mg
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Ingredient % of Wet ~ per Amount
Granulation tablet per
tablet
Chlorthalidone 36.724 35.714 25
Calcium Phosphate, 35.255 34.286 24
anhydrous
Starch 1500 15.424 15.000 10.5
Avicel PH102 10.283 10.000 7
Sodium Starch 2.314 2.250 1.575
Glycolate
(Intragranular)
Sodium Starch - 2.250 1.575
Glycolate
(Extragranular)
Magnesium Stearate - 0.500 0.350
Water (for 12% As Req'd - -
Starch Slurry)
Total 100% 100% 70mg
INACTIVE FORMULAS
DIRECT COMPRESSION FORMULAS
The following formulations are used in making single layer
tablets that may be subsequently adhesively joined to other
tablets. A Manesty 16 station Beta Press (single layer
rotary tablet press) is used to make the tablets. The three
formulations are directly compressible powder blends. The
blending is performed in a Patterson-Kelly "V" blender. The
tablets are compressed using 14 inch flat faced beveled edge
tablet punches to a hardness of 20-25 kiloponds. Weights in mg
of the granulation comprising each tablet follow:
Tablet 1 Mg.
Nu-Tab (Compressible sugar 30/35 N.F.) 194.00
Tablet 2
Dibasic calcium phosphate anhydrous 158.59
Magnesium stearate 2.79
PVP K-30 2.62
Total 164.00
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Tablet 3 Mg.
Lactose 316 Fast Flo 70.00
Microcrystalline cellulose (Avicel
PH102 ) 24.00
Crospovidone 4.00
Colloidal silicon dioxide 0.50
Hydrogenated vegetable oil 1.00
FD&C Red #40 Aluminum Lake 0.50
FLUID BED WET GRANULATION FORMULATION
The following formula is used to manufacture a wet inactive
granulation which is subsequently compressed into a single
layer tablet. The wet granulation is made using the following
fluid bed granulator procedure.
11. Screen the Starch 1500, Sodium Starch Glycolate and
Microcrystalline Cellulose through a US 20 mesh sieve.
12. Screen the Magnesium Stearate through a US 30-mesh sieve.
13. Weigh all of the ingredients. Balance.
14. Prepare 12% Starch slurry by adding the 150g of Starch
1500 to the 1100g of Water while stirring with a
Lightnin mixer with a propeller shaft. Mix for a minimum
of 10 minutes. Mix continuously during the granulation
procedure.
15. Place the '-~ Microcrystalline Cellulose, 22.5 g of Sodium
Starch Glycolate, and the remaining Microcrystalline
Cellulose into a Mendel Fluidbed Dryer/Granulator set up
with the 20 liter bowl and a top spray nozzle. Mix
for a minimum of 10 minutes before starting to spray. Set
up parameters are:
Inlet Temp: 60 to 70 C
Spray Rate: 25 to 35 g/min
Atomization Pressure: 1 bar
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16. Spray all of the Starch 1500 slurry on to the blend.
17. Dry the granulation to about 2% moisture.
18. Mill the dried granulation using the Comil with a 20 mesh
equivalent screen.
19. Place the milled granulation into a 4 quart V-Blender and
add the remaining 12.5g of Sodium Starch Glycolate and
mix for 5 minutes.
20. Add the Magnesium Stearate to the V-Blender and mix for 3
minutes.
The tablets are compressed on a Manesty 16 station Beta Press,
single layer rotary tablet press. The tablets are compressed
using 1-4 inch flat faced beveled edge tablet punches to a
hardness of 20-25 kiloponds. The tablet weight is 70.0 mg.
The following formula may be used to produce a granulation
that may produce tablet subunits of the invention.
INACTIVE WET GRANULATION
ingredient Percent per Amount per Amount per
Tablet Tablet (mg) Batch (g)
Starch 1500 15.00% 10.5 150
(Colorcon)
Microcrystalline 80.00% 56.0 800
Cellulose (Avicel
PH102) (FMC)
Sodium Starch 4.5% 3.15 45
Glycolate
Magnesium Stearate. 0.5% 0.35 5
(Mallinckrodt)
Water 1100*
(not part of final
blend)
1000 70 1000
The above active and inactive formulas are also suitable for
capsule filling. The formulas have to be adjusted to
accommodate the desired capsule fill volume.
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To make an adhesively bonded pharmaceutical dosage form, a
tablet may be made using one of the formulas above to compress
an amlodipine tablet using techniques well known in the art of
tablet manufacture. An inert tablet could be made using one
of the above formulas. One of the above formulations may be
used to manufacture a chlorthalidone tablet according to
standard techniques. Adhesive, such as, Mantrose-Heauser #4
Pharmaceutical Glaze (shellac) 45/200 is applied to both
mating sides of the inert tablet. The mating side of the
amlodipine tablet is joined to one of the inert tablet mating
sides and the chlorthalidone tablet (mating side) to the
other. Adhesive may or may not be applied to the mating sides
of the active tablets prior to mating to the inert tablet. The
tablets are allowed to dry with or without pressure applied
under ambient conditions or in a drying tunnel.
Numerous other means of creating the dosage forms of the
invention may be produced using the formulas given above to
allow production of tablets or capsules. An almost infinite
number of dosage forms may be produced according to the
invention using any of the many tablet and capsule formulas
that are known to those skilled in the art and that will be,
but have not yet been, developed.
Shellac solutions, preferably ranging from 29% w/w to 36% w/w
solids in a solvent comprising ethanol may be used as an
adhesive. An applicator is dipped into thoroughly-mixed
shellac and the shellac solution is applied to the joining
surfaces. A tablet subunit i,s joined to a tablet subunit(s);
a capsule subunit is joined to a capsule subunit(s); tablet
subunits may be joined to a capsule subunit(s) and tablet
subunits or capsule subunits are joined with linkers between
them. No limitation to the number of subunits or linkers is
intended.
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Examples of Methods of Joining the Subunits of the Dosage
Form:
1. About one ml. of the shellac solution is applied to the
entire joining surface of a tablet subunit. The joining
surface in the case of a tablet subunit is typically any
flat surface on the tablet subunit, but is not limited to
such a surface. About ten to twenty seconds are allowed
to elapse while some or all of the solvent (alcohol)
present in the shellac solution evaporates, leaving a
sticky adhesive residue on the tablet subunit. Then the
joining surface of the second tablet subunit is brought
into contact with the sticky surface of the first
subunit. The subunits are held together by light hand
pressure for about twenty seconds, and then allowed to
dry in the ambient air. '
2. An alternate method comprises placing the shellac
solution on the joining surface of both subunits at about
the same time, manually applying light pressure to both
subunits for twenty seconds, and allowing the dosage form
to air dry for about one minute to allow evaporation of
the solvent.
3. Similar procedures may be following in joining capsules
to each other, and utilizing linkers (subunits) to join
tablet to tablet, capsule to capsule, and tablet to
capsule, creating dosage forms in which the preformed
tablets and capsules then function as tablet subunits and
capsule subunits.
No limitation is intended in terms of the dilution of the
shellac, the choice of specific adhesive, the time or
degree of pressure applied to adhesively join the
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subunits, the time allowed for any solvent to evaporate,
the number of subunits joined, etc. The invention
expressly contemplates automated or semi-automated
methods of adhesively joining the subunits.
36
