U.S. patent application number 10/499280 was filed with the patent office on 2005-10-06 for release control type formed product.
Invention is credited to Ozeki, Yuichi.
Application Number | 20050220872 10/499280 |
Document ID | / |
Family ID | 19187881 |
Filed Date | 2005-10-06 |
United States Patent
Application |
20050220872 |
Kind Code |
A1 |
Ozeki, Yuichi |
October 6, 2005 |
Release control type formed product
Abstract
In order to provide a molded product capable of manifesting a
desired release control pattern of an effective ingredient by
direct tabletting method, a controlled release molded product was
devised characterized in having an outer layer and a plurality of
cores or a core partially provided with constrictions and portions
that can be substantially identified as a plurality of cores and
controlling release of the effective ingredient contained in the
core portion according to the distance from the outside of the
molded product to individual core. The molded product of the
present invention can also be used in a dividable controlled
release molded product in which the release property remains
unchanged after division by providing a structure coupling a
plurality of unit molded products and ensuring that the distance
from the division surface to the core is sufficiently longer than
the distance from the external reference plane on the molded
product surface that stipulates the distance from the outside of
the molded product to the core. It is possible to readily
manufacture the molded product of the present invention using
integral compression molding means having a double-structured
punch--punch consisting of a core punch and an outer punch
enclosing part or whole of the outer perimeter of the core
punch--above and below a die.
Inventors: |
Ozeki, Yuichi; (Aichi,
JP) |
Correspondence
Address: |
PATTERSON, THUENTE, SKAAR & CHRISTENSEN, P.A.
4800 IDS CENTER
80 SOUTH 8TH STREET
MINNEAPOLIS
MN
55402-2100
US
|
Family ID: |
19187881 |
Appl. No.: |
10/499280 |
Filed: |
May 10, 2005 |
PCT Filed: |
December 16, 2002 |
PCT NO: |
PCT/JP02/13154 |
Current U.S.
Class: |
424/468 ;
264/109 |
Current CPC
Class: |
B30B 11/34 20130101;
A61K 9/2095 20130101; A61K 9/2072 20130101; A61M 31/002 20130101;
A61J 3/10 20130101; B30B 11/08 20130101 |
Class at
Publication: |
424/468 ;
264/109 |
International
Class: |
D04H 001/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 19, 2001 |
JP |
2001-385864 |
Claims
1-8. (canceled)
9. A controlled release molded product comprising an outer layer
and a plurality of cores, wherein release of an effective
ingredient contained in the cores is controlled by varying a
distance from an outside of the molded product to each of the
plurality of cores arranged at a specific position.
10. The controlled release molded product of claim 9 further
comprising a coupling portion that joins the controlled release
molded product to a plurality of other controlled release molded
products that each comprise a core, wherein division of all of the
controlled release molded products from each other along the
coupling portion creates a division surface wherein a distance from
the division surface to any core is longer than a distance from the
outermost surface to the core of the molded product before
division.
11. The controlled release molded product of claim 9, wherein the
release of the effective ingredient is further controlled by a
property of a filler ingredient in the outer layer.
12. The controlled release molded product of claim 11, wherein the
filler ingredient in the outer layer is a matrix-type sustained
release base.
13. The controlled release molded product of claim 9, wherein no
filler ingredient having a release delaying property is contained
in the core.
14. The controlled release molded product of claim 9, having a
plurality of pulsed release properties.
15. The controlled release molded product of claim 9, wherein the
molded product is manufactured by a compression molding method
alone.
16. A controlled release molded product comprising an outer layer
and a core having at least one constriction such that a plurality
of cores are substantially formed, wherein release of an effective
ingredient, contained in the core portion, is controlled by a
distance from an outside of the molded product to each of the
plurality of cores substantially formed by the at least one
constriction of the core arranged at a specific position.
17. The controlled release molded product of claim 16, wherein no
filler ingredient having a release delaying property is contained
in the core.
18. The controlled release molded product of claim 16, having a
plurality of pulsed release properties.
19. The controlled release molded product of claim 16, wherein the
molded product is manufactured by a compression molding method
alone.
20. The controlled release molded product of claim 16, wherein the
release of the effective ingredient is further controlled by a
property of a filler ingredient in the outer layer.
21. The controlled release molded product of claim 20, wherein the
filler ingredient in the outer layer is a matrix-type sustained
release base.
22. The controlled release molded product of claim 16 further
comprising a coupling portion that joins the controlled release
molded product to a plurality of other controlled release molded
products that each comprise a core, wherein division of all of the
controlled release molded products from each other along the
coupling portion creates a division surface wherein a distance from
the division surface to any core is longer than a distance from the
outermost surface to the core of the molded product before
division.
23. A controlled release molded product comprising a plurality of
controlled release units each having an outermost surface and being
joined by coupling portions, with each unit comprising an outer
layer and at least one core at a specific position that comprises
an effective ingredient having a release pattern that is controlled
by a distance from the core to the outermost surface, the distance
being shorter than the shortest length between the core and a
surface created by separation of the units from each other along
the coupling portions.
24. The controlled release molded product of claim 23, wherein at
least one of the cores comprises a constriction that substantially
forms a plurality of cores from the original core.
25. The controlled release molded product of claim 23, wherein the
release of the effective ingredient is further controlled by a
property of a filler ingredient in the outer layer.
26. A method of making a molded product, the method comprising
preparing a unit having an outer layer and at least one core
disposed at a specific position in the outer layer to define a
distance from the at least one core to the outside of the outer
layer, and controlling release of the effective ingredient in the
core by selecting a material for the outer layer and selecting the
distance.
27. The method of claim 26, wherein the core is made with at least
one constriction.
Description
TECHNICAL FIELD
[0001] The present invention relates generally to a molded product
manufactured mainly by compressing powder or granular particles as
molding materials, and more particularly to a molded product in
which the release of the active ingredients can be controlled.
BACKGROUND ART
[0002] In therapeutic, recent years have seen ongoing efforts to
develop solid preparations called time-specific controlled release
preparations to enhance control of the absorption process such as
reducing side effects and improving the targeting of absorption in
the digestive system. While including sustained release and enteric
preparations in broad sense, the preparations generally refer to
time lag or pulsed preparations.
[0003] In the case of pharmaceutical drugs, there exist generally
compounds for new drug candidates and drug substances of commercial
drugs called active components (hereafter represented as "active
components") having various physicochemical and biopharmaceutical
properties, requiring various release control (in vitro and in
vivo) technologies appropriate for the purpose of the therapy. By
setting drug release patterns (dissolution patterns described
later; synonym for dissolution property) adapted for the purpose of
therapy, it is possible to (1) enhance the efficacy by
chronopharmacotherapy and reduce side effects, (2) avoid the first
pass metabolism caused by local release in the colon, rectum, etc.,
(3) enhance the biological applicability of peptide drugs and the
like and (4) conduct localized treatment of specific areas, not
only rationalizing treatment and rendering it more adequate but
also leading to improved patients' QOL (Quality of Life). To
establish technologies to allow control over release of such active
components, therefore, needs have been voiced continuously to (1)
create wide-ranging dissolution patterns, (2) build a highly
accurate release control technology and (3) downsize the
dissolution control technology (Kobayashi; PHARM TECH JAPAN vol. 17
No. 1 2001).
[0004] The time-controlled explosion system (TES) developed by Hata
et al. (Hata, Ueda: PHARM TECH JAPAN vol. 4 1988) is among systems
that release drug after a given lag time, which is one example of
conventional time-specific controlled release preparations. The
system has a three-layer structure requiring a drug layer, a
swelling layer and a water-insoluble polymer layer. The preparation
allows for rapid drug release by using a swelling agent to absorb
water penetrating inside the system from outside through the
polymer coating and by collapse of the polymer coating due to
swelling force resulting from hydration of the swelling agent.
[0005] As another time-specific controlled release preparation, a
preparation of three-layer structure, described in Japanese Patent
Application Laid-Open Publication No. 7-2650, is also described as
having an enteric coating as the outer layer, an inner layer
thereinside for allowing sustained release and a core containing
the drug. This preparation also elutes rapidly after a given time
lag.
[0006] Pulsincap, developed by R P Sherer, is a preparation that
achieves time-specific release control differently from the
aforementioned multi-layer coating method. This preparation has a
hydro-gel polymer plug fitted to an insoluble capsule, thus
controlling the release time by the length of the gel. Although
each of such preparations can rapidly release the active component
after a given lag time, a number of problems have yet to be
addressed in terms of practical use, including a special capsule
required and limited volume thereof.
[0007] While an example of time-specific controlled release
preparations was described above as conventional time-lag
preparation, these preparations are saddled with many problems. In
the case of a time-specific controlled release preparation
constituted by a multi-layer coating, for instance, variations in
coating thickness between layers result in variations in
preparation's dissolution property. This means that unless the
coating thickness is precisely controlled, it is impossible to
precisely control the dissolution property. In actuality, however,
as long as the manufacturing method or "coating" is used,
variations in film forming are unavoidable. More specifically, film
layer thickness varies from one preparation lot to another. Even
one preparation has a different thickness from one area to another
(in general, difference in coating thickness tends to occur between
the tablet edge and the remaining areas). In light of the above,
these preparations are generally often used for granules that are
easier to film-coat, and one must say that applying the
preparations to tablets themselves is technically difficult.
Besides, stacking a number of coating layers is intricate from the
viewpoint of manufacturing cost and technically difficult, making
it more costly than preparations showing an ordinary
dissolution.
[0008] Next, a description will be given of time-specific
controlled release preparations having the release property of
repeating dissolution a plurality of times (multi-pulse). The
aforementioned method of repeated coating requires adjustment of
coating thickness in consideration of increase in granule volume
caused by coating or adjustment of main component concentration
according to the coating thickness if there exists an active
component thereinside. Further, the more multi-layer coatings, for
example, the more difficult it becomes to downsize preparations. In
other words, the more precision is required in dissolution control,
the more intricate and complicated the manufacturing steps become,
making the method hardly industrially viable.
[0009] Conventional controlled release preparations, in which a
tablet is repeatedly coated, is further problematic in that the
tablet is not dividable (i.e., tablet cannot be split). Division of
tablets in the medical workplace is widely used to tailor the drug
concentration to pharmacokinetics of individual patients. While a
dividable tablet commonly has a concave line (scored line) on the
surface and dividing the tablet along the line allows for
administration of half tablet. However, a controlled release
preparation produced by coating cannot maintain its controlled
release properties if it is divided or split when administered.
That is, dividing the tablet results in direct exposure of
individual coating layers on the split surface to the outside
world, making it impossible to control drug release.
[0010] On the other hand, Japanese Patent Application Laid-Open
Publication Nos. 8-157392 and 2000-128779 disclose preparations
that have a time lag and a plurality of pulses by adjusting, in
advance, a plurality of granules having different dissolution
properties, mixing the plurality of granules and filling the
mixture in a capsule, etc. for use as preparation. However, not
only the granules in the disclosed preparation involve variations
in dissolution attributed to coating, but also it is apparent from
the fact that the preparation comprises a plurality of granules
having different dissolution properties that variations in
dissolution become more obvious. As an alternative method, it is
theoretically possible to arrange a plurality of cores in layered
form by repeating the conventional method of manufacturing a
press-coated tablet. That is, this method consists of manufacturing
a multi-core press-coated tablet by manufacturing a press-coated
tablet in advance and using the tablet as a core in a new
press-coated tablet. However, the present method requires a certain
size of the core tablet, making the upsizing of the tablet
unavoidable. For example, if a core tablet of the first layer is 6
mm in diameter with the tablet, into which the core tablet is
introduced (introduced with 2 mm gap on each side of the core
tablet of 6 mm in diameter), being 10 mm in diameter and if the
same method is repeated up to the third layer, the final tablet
size is 14 mm, making the downsizing impossible and resulting in
departure from the tablet size generally said to be swallowable.
Naturally, manufacturing cost becomes inevitably higher, making the
method hardly feasible. Besides, the tablet is undividable due to
its structure as with coated-type release preparations.
DISCLOSURE OF THE INVENTION
[0011] In order to solve the aforementioned problems with the
conventional art, the present inventor earnestly conducted studies
to provide a molded product that stably offers a desired controlled
release profile of the effective ingredient using a manufacturing
method by simple direct tabletting rather than the coating method.
As a result, they devised a molded product, noting the localization
of substantially a plurality of cores containing an effective
ingredient inside the molded product, in which the plurality of
cores were localized at specific positions. That is, the present
invention is a controlled release molded product characterized in
having an outer layer and a plurality of cores, wherein the release
of the effective ingredient contained in the core portions can be
controlled by varying the distance from the outside of the molded
product to the individual cores arranged at specific positions, or
a controlled release molded product characterized in having an
outer layer and a core partially provided with constrictions and
portions that can be substantially identified as a plurality of
cores, wherein the release of the effective ingredient contained in
the core portion is controlled by varying the distance from the
outside of the molded product to the individual portions that can
be substantially identified as a plurality of cores arranged at
specific positions. Further, in order to render dividable the
controlled release molded product of the present invention, they
studied the arrangement of cores and scored line so as to maintain
the release property thereof after division, and as a result,
arrived at devising a molded product provided, as described below,
with scored line so as to ensure that the distance from the outside
of the molded product to the cores remains unchanged before and
after division. That is, this molded product is a dividable
controlled release molded product characterized in having a
structure coupling the plurality of controlled release molded
products of the present invention and being dividable along the
coupling portion as division surface, with the distance from the
division surface to any core in individual unit molded products
being sufficiently longer than the distance from the external
reference plane on the molded product surface that stipulates the
distance from the outside of the molded product to cores.
[0012] The controlled release molded product of the present
invention can be readily manufactured using integral compression
molding means having double-structured punches consisting of a core
punch and an outer punch enclosing part or whole of the outer
perimeter of the core punch.
[0013] For example, a molded product can be transformed into a
controlled release molded product having a plurality of given
release peaks by linearly scattering cores from the outside of the
molded product toward the inside thereof and allowing the outer
layer and/or cores to dissolve successively from the outside
because the molded product erodes from the outside toward the
inside.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIGS. 1A to 1C illustrate variations of a controlled release
molded product according to the present invention in which
sectional views of the finished molded products are shown. The
shaded areas represent the cores and the remaining areas
representing the outer layer, FIGS. 1A-1 to 1A-7 are examples of
molded products having a core partially provided with constrictions
and portions that can be substantially identified as a plurality of
cores. FIGS. 1B-1 to 1B-7 are examples of molded products having a
plurality of cores, and FIG. 1C-1 is an example of molded product
in which cores of the types shown in FIG. 1A and FIG. 1B are used
in conjunction; these figures also constitute, as such, examples of
tip portions of double-structured split punch used to manufacture
the molded product of the present invention, and in that case, the
shaded areas represent a core punch, and the remaining areas
representing an outer punch;
[0015] FIGS. 2A-2N illustrate explanatory views of punch tip
operations showing an example of a manufacturing method of the
controlled release molded product of the present invention, with
only the core punch shown by oblique lines and oblique lines as
cross section omitted for convenience;
[0016] FIGS. 3A to 3C illustrate examples of the controlled release
molded product of the present invention, FIG. 3A being a side
schematic view, FIG. 3B being a top view, and FIG. 3C being a
perspective view of the cross-section of the molded product;
[0017] FIG. 4 is an overall front sectional view of a common rotary
compression-molding machine, except that the sectional views of the
punch, the vertical shaft, and the hopper are not shown;
[0018] FIG. 5 is a schematic plan view showing the top side of a
turntable in an embodiment of the rotary compression-molding
machine capable of manufacturing the controlled release molded
product of the present invention;
[0019] FIG. 6 is a schematic view including a partial sectional
view and showing the operational mechanism of upper and lower
punches by developing the turntable in an embodiment of the rotary
compression-molding machine capable of manufacturing the controlled
release molded product of the present invention;
[0020] FIGS. 7A to 7D illustrate an example of a double-structured
punch (lower punch) capable of manufacturing the controlled release
molded product of the present invention, FIG. 7A being a front
schematic view, FIG. 7B being a front sectional view, FIG. 7C being
a side view, and FIG. 7D being a front view of the punch tip;
[0021] FIGS. 8A and 8B illustrate a residual powder or granular
particles removal device of the present invention, FIG. 8A being a
bird's-eye view, and FIG. 8B being a top view;
[0022] FIGS. 9A to 9C illustrate variations of the controlled
release molded product of the present invention in which sectional
views of the finished molded products are shown, with the shaded
areas representing the cores and the remaining areas representing
the outer layer, and the dashed lined representing the division
surface. The arrows represent the external reference plane. FIGS.
9A-1 to 9A-4 show examples of molded products that will be divided
into two parts, FIGS. 9B-1 and 9B-2 being examples of molded
products that will be divided into four parts, and FIG. 9C-1 and
9C-2 being an example of a continuous body of dividable controlled
release molded products; these figures also constitute, as such,
examples of embodiments of tip portions of double-structured split
punch used to manufacture the molded product of the present
invention, and in that case, the shaded areas represent the core
punch, the remaining areas represent the outer punch, and the
dashed lines represent convex lines for forming scored lines.
[0023] FIG. 10 is a dissolution pattern diagram for a controlled
release molded product, in pure water, of manufacturing example 1
using hydroxypropylcellulose for the outer layer, the closed
circles representing the dissolution rate (%) of thoeophyline, and
the open circles representing the dissolution rate (%) of
thoeophyline per unit time; and
[0024] FIG. 11 is a dissolution pattern diagram for a controlled
release molded product, in test solution No. 2 (ph6.8), of
manufacturing example 2 using Eudragit for the outer layer, the
closed circles representing the dissolution rate (%) of
thoeophyline, and the open circles representing the dissolution
rate (%) of thoeophyline per unit time.
BEST MODE FOR CARRYING OUT THE INVENTION
[0025] In this description, not only the active ingredient in drugs
(effective ingredient, main ingredient) and main ingredient in
foods but also any ingredient for which release from a molded
product is controlled is encompassed by the term "effective
ingredient" whereas ingredients other than effective ingredient,
namely, various additives such as filler, binder, disintegrator,
lubricant and anti-agglutinator that are regularly used in the
fields of formulation technology and molded product manufacturing
technology are collectively referred to as "filler
ingredients."
[0026] The controlled release molded product of the present
invention is characterized in having an outer layer and
substantially a plurality of cores whereby the release of the
effective ingredient contained in the core portions is controlled
according to the distance from the outside of the molded product to
individual portions arranged at specific positions. The term
"substantially a plurality of cores" may be either a plurality of
cores or a core partially provided with constrictions and portions
that can be substantially identified as a plurality of cores.
[0027] Here, the term "a plurality of cores" refers to a plurality
of cores that are literally separated from one another (refer to
FIGS. 1B1 to 1B7). On the other hand, the term "core partially
provided with constrictions and portions that can be substantially
identified as a plurality of cores" refers, in the present
description, to embodiments as shown in FIGS. 1A1 to 1A7, which is,
namely, the case of a core that, while being a single connected
core if viewed as a single molded product, appears to be several
cores coupled together as a result of "constrictions" present in
the core shape. In the case of such a core, there are a plurality
of peaks in the effective ingredient release profile in the actual
administration environment due to substantial isolation between
cores or change in release rate, for example, as a result of
swelling of the outer layer ingredient around the cores.
[0028] It should be noted that there may be, in a molded product, a
single core or a plurality of cores that are partially provided
with constrictions and portions that can be substantially
identified as a plurality of cores (refer to FIGS. 1A1 to 1A7).
Further, such cores may coexist with other ordinary cores (refer to
FIGS. 1C-1). The present invention includes all these embodiments.
It should be understood that the same holds true for the dividable
controlled release molded product described later.
[0029] In the present invention, the distance from the outside of
the molded product to a core or portion that can be substantially
identified as a core (hereinafter collectively referred to as
"core") is the shortest distance from the outside of the molded
product to such a core. The molded product surface, or the starting
point thereof, that determines this shortest distance is assumed to
be the external reference plane that stipulates the distance from
the outside of the molded product to cores. This external reference
plane may be viewed not only as a plane but also as a point and may
also exist in a plurality. In the present invention, cores are
arranged inside the molded product including the molded product
surface. The arrangement of the cores is determined by the intended
release profile. That is, the release profile of the molded product
of the present invention is determined by positions at which
individual cores are arranged. This means that the first release
occurs from the core closest to the outside of the molded product,
followed successively by those toward the inside of the molded
product. In the case of a donut-shaped molded product in troche
form, for example, external reference planes often exist not only
on the outer perimeter surface outside the molded product but also
at hole portions thereinside. Since core-to-core release time lag
depends on the difference in distance from the outside of the
molded product to each individual core, the larger the difference
in distance, the longer the time from the first to next release.
Here, core positions can be freely set according to the desired
release profile. Needless to say, the number of release peaks
depends on the number of cores. While specific examples of core
arrangement are shown in FIG. 1, there are an indefinite number of
arrangement patterns, including those in which a plurality of cores
are linearly scattered from the outside of the molded product
toward the inside thereof with one external reference plane (e.g.,
typically FIGS. 1A-1 and 1B-2) and others in which cores are
arranged from several directions with a plurality of external
reference planes (e.g., typically FIGS. 1B-4 and 1B-7).
[0030] The dividable controlled release molded product of the
present invention is characterized in having a structure in which a
plurality of controlled release molded products are coupled
together and dividable along the coupling portion as the division
surface, with the distance from the division surface to any core in
the individual unit molded products being sufficiently longer than
the distance from the external reference plane on the molded
product surface that stipulates the distance from the outside of
the molded product to cores. The reason lies in that, in the
presence of a core whose distance to the division surface is not
sufficiently longer than the distance from the external reference
plane, the external reference plane of the core becomes a division
surface as a result of division, possibly changing the shortest
distance from the outside of the molded product. Since a molded
product cannot always be divided uniformly, a "sufficiently long"
configuration is needed to allow for those variations. Here, the
term "sufficiently long", while being dependent on the molded
product size, is probably, for example, at least over 1 mm longer,
and preferably at least over 2 mm longer. Thus, the release profile
of individual molded products after division (unit molded products)
maintains the same profile as with the release profile of the
controlled release molded product before division. It should be
noted that the term "having a structure coupling the plurality"
does not mean that the molded product was manufactured by actually
coupling individual unit molded products together. Rather, it
denotes that individual unit molded products are appear to be
coupled together. Similarly, the term "coupling portion" is not the
coupling surface created by actual coupling but the apparent
coupling surface anticipated as the boundary surface of a unit
molded product. The dividable controlled release molded product of
the present invention preferably has a concave scored line at the
division position and can be divided at the scored line into
separate unit molded products.
[0031] The Embodiments as shown in FIG. 9 are examples of dividable
controlled release molded products. FIGS. 9A-1 to 9A-4 are examples
of molded products from which two controlled release molded
products can be obtained as a result of division from the division
surface (division line portion) shown by a dashed line, whereas
FIGS. 9B-1 and 9B-2 are examples of molded products that are
similarly dividable into four parts. FIGS. 9C-1 and 9C-2 are
continuous bodies of controlled release molded products arranged
linearly and continuously, constituting examples of molded products
dividable into individual unit molded products at coupling portions
having a division line. It should be noted that the external
reference planes are indicated by arrows in FIG. 9. In all
post-division and pre-division molded products, the shortest
distance from the outside of the molded product to the core is the
distance from these external reference planes. Although only
natural, there may be, in the present dividable controlled release
molded product, a plurality of cores, a core partially provided
with constrictions and portions that can be substantially
identified as a plurality of cores or both thereof coexisting with
each other.
[0032] In the present invention, it is further possible to control
release of the effective ingredient by selecting an appropriate
filler ingredient. That is, in addition to release control by the
distance from the outside of the molded product to the core
containing effective ingredient, release control by filler
ingredient can be concurrently used. Release control by selection
of a filler ingredient not only controls release rate of the
effective ingredient and release time lag by the filler ingredient
property but also plays an important role, as described later, in a
core partially provided with constrictions and portions that can be
substantially identified as a plurality of cores. Here, the filler
ingredient controlling release rate of the effective ingredient can
be contained in the core or the outer layer.
[0033] For example, use of an effective ingredient and sustained
release filler ingredient in the core adjusts the diffusion speed
of the effective ingredient and also makes it possible to switch
each pulse release to sustained release. Further, by using a filler
ingredient low in solubility for the outer layer, it is possible to
prolong the release time lag between pulses.
[0034] When a matrix-type sustained release base is used primarily
as filler ingredient in the outer layer, embodiments as those of
the present invention are particularly useful that use a core
partially provided with constrictions and portions that can be
substantially identified as a plurality of cores. In general, as
far as the release pattern is concerned, a molded product
consisting of a matrix type sustained release base and effective
ingredient diminishes in size as a result of gradual erosion as the
molded product surface becomes gelated without suddenly collapsing
as with ordinary tablets. Therefore, when the base is used, the
constricted portions of the core are brought closer to each other
or bonded together as a result of swelling or gelation of the outer
layer ingredient surrounding the core due to water absorption or a
combination thereof, thus allowing for the core to serve the
function similar to that of a plurality of cores. That is, after
absorbing water, the matrix type sustained release base prevents
sudden release of the effective ingredient and switch the release
to slow one (sustained release) due to this property. Among matrix
type sustained release bases are hydroxypropylcellulose,
hydroxypropylmethylcellulose, methylcellulose, carboxy
methylcellulose sodium--cellulose derivertives--and polyvinyl
alcohol. These ingredients can be used alone or in combination with
each other and may be used concurrently with an ordinary filler
ingredient.
[0035] Further, the use of a base with the above property in an
ordinary molded product having a plurality of cores provides a
preparation having a plurality of release pulses as the overall
release pattern while at the same time ensuring sustained release
of drug within the matrix. Conversely, to release the core
ingredient by dissolving the molded product gradually from the
outside, it suffices to use a slow-dissolving polymer for the outer
layer, including such ingredients as natural polymers, synthetic
polymers and synthetic elastomers (p. 36 Practical Drug Delivery
System by Kohei Miyao). For example, poly lactic acid and copolymer
of lactic acid-glycolic acid are among them. These ingredients can,
as with the matrix bases, be used alone or in combination with each
other and may be used concurrently with an ordinary filler
ingredient.
[0036] The outer layer ingredient used in the molded product of the
present invention thus has a considerable impact on the release
pattern of the effective ingredient from the cores. On the other
hand, the cores of the present invention are generally assumed to
contain an effective and filler ingredients or substantially an
effective ingredient alone. As described earlier, while a similar
sustained release filler ingredient, as illustrated in relation to
the outer layer, may be used in the cores, it is preferred that
effective ingredient release from the cores be fast, since the
molded product of the present invention has its release controlled
by the positioning of individual cores. Among ingredients that
allow fast release are sugars typified by lactose and crystalline
cellulose that serves also as a disintegrator. Conversely, it is
not preferred for the cores to contain a filler ingredient having
the property of delaying effective ingredient release from the
cores, since these results in overlap with release as controlled by
the positioning of the core and therefore makes it difficult to
obtain the intended release profile. It should be noted that the
term "release delay", although not precisely definable because the
release rate varies due, for example, to the release property of
the effective ingredient itself, is defined in the present
description as intentional delay of the release rate of the
effective ingredient itself, whereas the term "filler ingredient
having the property of delaying release" denotes an ingredient
capable of delaying the release rate of the effective ingredient by
the filler. In actuality, while filler ingredients include polymers
such as the aforementioned matrix type sustained release bases,
they are not limited thereto.
[0037] A description will be given below of application of the
present invention primarily to pharmaceutical drugs.
[0038] It suffices for the cores (including the portions that can
be substantially identified as cores) in the present invention to
be shaped and sized dependening primarily on the intended release
profile and release amount. While it is preferred to reduce the
size in terms of preventing upsizing of the molded product as a
whole, exceedingly small cores are not preferred either, as
downsizing the cores more than necessary can readily create a
bottleneck to smooth charging of the core ingredients in the
molding step and physical property limitations of powder or
granular particles for the core ingredients become more rigorous.
After all, in the case of round cores, it suffices to design them
to be 3 mm to 0.5 mm in diameter and preferably 2 mm to 1 mm in
diameter. Next, the shape of cores is not limited, and it suffices
to shape them so as to fit the intended release pattern. While
various combinations may be possible such as identical shape and
size for all cores in the molded product and different shapes and
sizes therefor, it is preferred that they be shaped in
consideration of difficulties involved in machining the punch tip
shape of the punch described later in relation to the manufacturing
method or ease of powder or granular particles charging in the
manufacturing steps.
[0039] On the other hand, while the shape and size of the
controlled release molded product of the present invention are
affected by the shape and size of the cores, it is preferred that
the molded product be shaped and sized so as to be easy to hold or
swallow. The shape thereof is not specifically limited, but it is
preferred that the molded product be a round or oval preparation
notably in pharmaceutical drugs. As for the size thereof, on the
other hand, it suffices, in the case of a round tablet, to design
the tablet to be, for example, 13 mm or less in diameter or 4 mm to
13 mm in diameter, preferably 5 mm to 11 mm in diameter and more
preferably 6 mm to 9 mm in diameter.
[0040] Various additives may be used for the cores and the outer
layer of the controlled release molded product of the present
invention including filler, binder, disintegrator, lubricant and
anti-agglutinator (already defined collectively as "filler
ingredients") that are regularly used in the fields of formulation
technology, although this partly overlaps with the previous
description. As for the addition amount thereof, such additives can
be used without any problem in amounts based on the knowledge
regularly used in the field of formulation technology. Effective
ingredient can be added to not only the cores but also the outer
layer, thus making it possible to provide a release pattern having
release peaks in a scattered manner while continually maintaining
effective ingredient release or a special molded product that
contains different effective ingredients in the outer layer and the
cores.
[0041] Wide-ranging pharmaceutical drugs can be contained in the
outer layer and the cores of the controlled release molded product
of the present invention as an effective ingredient. Among
pharmaceutical drugs for exploiting the release property of the
preparation are nifedipine, a preventive drug for angina pectoris
attack (chest pain) in the early morning, and morphine sulfates,
cancer pain treatment drugs of which continuous drug release is
demanded. However, it is not always necessary to select a
pharmaceutical drug in consideration of the release property of the
preparation, and any pharmaceutical composition may be chosen as
long as oral administration is possible.
[0042] While ingredients to be contained in the outer layer and the
cores may be used as is, granular substance may be prepared once by
granulation by a normal method and sized as necessary for use. It
is also possible to prepare granular substance by coating a drug's
active ingredient, functional food ingredient or ordinary food
ingredient together with a binder on an inactive carrier. Further,
granular substance may be coated as necessary with sustained
release coating, time-lag coating, enteric coating, gastric
coating, water soluble coating, sugar coating, etc.
[0043] It should be noted that the controlled release molded
product of the present invention is not limited to drugs and can be
applied to the fields of foods, sanitary products and so on. It
suffices to determine such as the size/shape of the cores or the
entire molded products, ingredients to be contained and so on
according to individual fields and purposes. The controlled release
molded product of the present invention is not limited to those
that can be orally ingested and would find application, for
example, in the field of sanitary products, to a molded product
controlling effective ingredient release in a solution
environment.
[0044] A detailed description will be given next of a method of
manufacturing the controlled release molded product of the present
invention.
[0045] It should be noted that, in the present description, the
term "powder or granular particles" is used to refer to all molding
materials including powders and granules, except where the term
"powder" is particularly commonly used.
[0046] The controlled release molded product of the present
invention can be manufactured by compression molding means provided
with a die having punches thereabove and therebelow, each of the
punches having a double structure (details shown in the punch
structure described later) consisting of a core punch and an outer
punch enclosing part or whole of the outer perimeter of the core
punch and both the core and outer punches being slidable and
manipulatable for compression operation. That is, it is possible in
the present invention to compression-mold a press-coated type
molded product using only a set of die and punches through a series
of steps. For this reason, the molding method employed in the
present invention is called integral molding method. The term has a
meaning in contrast with conventional press-coated molded products
manufactured by molding a core in advance and supplying it in the
middle of molding step.
[0047] The present integral molding method keeps the core in
position and allows for their accurate localization, thus
eliminating problems such as variations in the release pattern as a
result of core "displacement." That is, the controlled release
molded product of the present invention can also be worded as a
"set of controlled release molded products, free of core
"displacement", whose usefulness becomes apparent when grasped as a
set of many." In the present description, the term "set" conveys a
meaning of a number of mass-produced molded products and is more
specifically 100 pieces or more or 1000 pieces or more under
certain circumstances or can be 10000 pieces or more. The method of
the present invention can freely change the size/shape of the core,
making it possible to control release dependently on the core
size/shape, namely, control the release amount of the effective
ingredient dependently on the core. While maintaining the constant
concentration of the effective ingredient in a plurality of cores,
it is also possible to change the release amounts or release
profile of the effective ingredient from individual cores by the
core size and shape alone.
[0048] Next, a detailed description will be given of an example of
an embodiment deemed most preferred as the method of manufacturing
the controlled release molded product of the present invention
mainly with reference to FIG. 2. Wordings such as a powder or
granular particles for a first outer layer OP1 and a powder or
granular particles for a second outer layer OP2 are not used to
mean different powder or granular particles but used for
convenience to make a distinction between the portions. It should
be noted that the term "core" includes the plurality of cores
and/or the core partially provided with constrictions and portions
that can be substantially identified as a plurality of cores.
[0049] First, with lower core and outer punches 5A and 5B lowered
(FIG. 2A), the lower outer punch 5B is raised while supplying a
powder or granular particles for the first outer layer OP1, filling
a first outer layer space 201 partially enclosed by the lower outer
punch 5B and above the lower core punch 5A, with the powder or
granular particles for the first outer layer OP1 (FIG. 2B). After
raising the lower core punch 5A as necessary and thus discharging
the excess powder or granular particles for the first outer layer
OP1 out of a die 3, an upper core punch 4A and the lower core punch
5A are moved to engage each other for temporary compression (FIG.
2C), thus temporarily molding the first outer layer. (Outer layer
molding step)
[0050] Next, with the temporary molded product of the first outer
layer OP1 held by the lower core and outer punches 5A and 5B, a
powder or granular particles for cores NP is supplied into a core
space 202 partially enclosed by the lower outer punch 5B and above
the temporary molded product of the first outer layer OP1 by
lowering the lower core punch 5A as necessary (FIGS. 2E and 2F).
Then, after raising the lower core punch 5A as necessary and thus
discharging the excess powder or granular particles for the cores
out of the die 3, the upper and lower core punches 4A and 5A are
moved to engage each other for temporary compression (FIG. 2G),
thus temporarily molding the temporary molded products of the first
outer layer and the core. (Outer layer/core molding step)
[0051] Further, with the temporary molded products of the first
outer layer and the core held by the lower core and outer punches
5A and 5B, a powder or granular particles for the second outer
layer OP2 is supplied into a second outer layer space 203 above and
around the temporary molded products of the first outer layer and
the core within the die 3 (FIGS. 2J and 2K) by lowering the lower
punch (both the lower core and outer punches 5A and 5B or the lower
outer punch 5B) (FIG. 21). The temporary molded products of the
core held on the temporary molded products of the first outer layer
are allowed to be partially covered with the powder or granular
particles for the outer layer and the temporary molded products of
the outer layer (FIG. 2K), and the excess powder or granular
particles for the second outer layer OP2 is discharged as necessary
out of the die 3 (FIG. 2L). It should be noted that the powder or
granular particles for the second outer layer OP2 can be supplied
after sufficiently lowering the lower outer punch 5B first such
that the temporary molded products of the first outer layer and the
core are apparently pushed up. Then, the upper punch (both the
upper core and outer punches 4A and 4B) and the lower punch (both
the lower core and outer punches 5A and 5B) are moved to engage
each other for precompression (temporary compression) of the entire
molded product consisting of the first outer layer, the cores and
the second outer layer as necessary, eventually followed by main
compression (FIG. 2M). (Overall molding step)
[0052] The step shown in FIG. 2N is for ejecting the completed
molded product.
[0053] It should be noted that there is an alternative method of
supplying the powder or granular particles for the first outer
layer into a space created by lowering the lower core punch 5A
alone without moving the lower outer punch 5B.
[0054] It should be noted that outer punch tip portions (6B, 7B)
correspond to a circumferential edge 76 of a completed molded
product shown in FIG. 3 and may be flat depending on the embodiment
of the molded product. If they are not flat as shown in FIG. 2, it
is preferred, to prevent contamination between the powder or
granular particles for the outer layer and the cores, that steps
(FIGS. 2D and 2H) of removing residual powder or granular particles
57 and 58 remaining on an upper surface 7B of the lower outer punch
be further added after supply of the first outer layer OP1, during
compression molding thereof (during temporary molding) or
thereafter and after supply of the cores NP, during compression
molding of the first outer layer OP1 and the cores NP (during
temporary molding) or thereafter. The present removal steps can be
carried out with compressed air injection and suction, brushing,
scraping, etc. or a combination thereof. These are referred to as
residual powder or granular particles removal means.
[0055] In addition to the above, a variety of embodiments would be
possible for the method of manufacturing the controlled release
molded product of the present invention. For example, there is a
method of temporarily molding, with the powder or granular
particles for the fist outer layer OP1, a pot-shaped molded product
first that can accommodate the powder or granular particles for the
plurality of cores NP, introducing a given amount of the powder or
granular particles for the cores NP into the pot-shaped molded
product and further covering the powder or granular particles for
the cores NP with the powder or granular particles for the second
outer layer OP2, followed by compression. Alternatively, it would
be possible, for example, to temporarily mold the powder or
granular particles for the cores alone and hold the temporary
molded product by the upper core and outer punches first, then
place the core on top of the lower punch (the lower core and outer
punches) filled with the powder or granular particles for the first
outer layer OP1 and finally cover the core on all sides and on the
top with the powder or granular particles for the second outer
layer OP2, followed by main compression.
[0056] For details regarding the above alternative embodiments,
please refer to the manufacturing methods, described in
International Publication No. W0/01/98067, for which the present
inventors applied for a patent earlier. It should be noted that
while these manufacturing methods differ from the aforementioned
example in punch operation method, powder or granular particles
supply/charging timings and so on, they can be carried out with
punches and die similar to those used in the first example of the
manufacturing method.
[0057] The method of manufacturing the controlled release molded
product of the present invention can be basically readily carried
out using a hydraulic press, etc. if the upper and lower punches
and die as described earlier are available. The manufacturing
method can be readily implemented by performing, in accordance with
the sequence of steps of the present invention, a series of
steps--steps of manually and/or automatically moving the upper and
lower punches or the core and outer punches to predetermined
positions, charging intended powder or granular particles and
pressing the powder or granular particles so as to sandwich them
from above and below with a hydraulic press in accordance with the
sequence of steps of the present invention. In addition thereto,
the manufacturing method can be carried out using the apparatus for
manufacturing a press-coated molded product as described below.
[0058] The apparatus for manufacturing the controlled release
molded product of the present invention has adopted the basic parts
of the mechanism and construction of previously common rotary
compression molding machine. Namely, the machine has a rotatable
turntable, provided with a die having die holes on the turntable
and being designed to compress powder or granular particles charged
into the die by holding upper and lower punches above and below the
die so as to be vertically slidable, moving the upper and lower
punches to engage each other and pressing the powder or granular
particles with the punch tips left inserted in the die. Further,
the apparatus uses, for the upper and lower punches, a double punch
having a double structure consisting of a core punch and an outer
punch enclosing part or whole of the outer perimeter of the core
punch, with both the core and outer punches being slidable and
manipulatable for compression operation, comprises means for moving
the core and outer punches of the double punch and means for
allowing manipulation of the core and outer punches for compression
operation and is constructed so as to perform the aforementioned
manufacturing method through a series of steps.
[0059] That is, when the invention is embodied in a rotary
compression molding machine characterized in having a rotatable
turntable provided with a die having die holes on the turntable,
the powder or granular particles charged into the die are
compressed by holding upper and lower punches above and below the
die so as to be vertically slidable, moving the upper and lower
punches to engage each other and pressing the powder or granular
particles with the punch tips left inserted in the die. The machine
would include, for both the upper and lower punches, a double punch
having a double structure consisting of a core punch and an outer
punch enclosing part or whole of the outer perimeter of the core
punch, with both the core and outer punches being slidable and
manipulatable for compression operation. A means for moving the
core and outer punches of the double punch and means for allowing
manipulation of the core and outer punches for compression
operation is also provided. The machine also provides, on the same
turntable, supply/charging portions respectively for powder or
granular particles for the outer layer and the cores, compression
molding portions for the powder or granular particles for the cores
and/or the outer layer and compression molding portion for the
entire molded product. In the present manufacturing apparatus,
there are generally two or more supply/charging portions for powder
or granular particles for the outer layer.
[0060] It should be noted that a residual powder or granular
particles removal device may be provided for removing powder or
granular particles remaining on the lower outer punch and/or the
molded product, depending on the shape of the punch tips.
[0061] The present manufacturing apparatus, if described more
specifically, is a rotary compression molding machine characterized
in comprising a portion for supplying a first powder or granular
particles into a space roughly enclosed by the lower outer punch
and above the lower core punch, a portion for subsequent
compression molding of the first powder or granular particles by
the upper and lower core punches, a portion for supplying a second
powder or granular particles into a space roughly enclosed by the
lower outer punch and above the lower core punch (or above the
molded product), a portion for subsequent compression molding of
the second powder or granular particles by the upper and lower core
punches, a portion for supplying a last powder or granular
particles into a space within the die and a portion for subsequent
compression molding of the entire molded product by the upper and
lower core and outer punches.
[0062] To describe, in further detail, the apparatus for
manufacturing the controlled release molded product of the present
invention, descriptions will be given in succession beginning with
conventional rotary compression molding machine.
[0063] If the machine is shaft-driven, for example, a rotary
compression molding machine has a vertical shaft 101, supported by
a bearing 100, arranged at the center portion of a main body frame
111, with a motor 102 transmitting rotational drive force to the
vertical shaft and a turntable 103--splittable into two functional
parts--fixed near the vertical shaft, as shown in FIG. 4. Further,
there are provided an upper punch holding portion 104, located on
the upper portion of the turntable, for holding an upper punch so
as to be vertically slidable and a lower punch holding portion 105,
located on the lower portion of the turntable, for holding a lower
punch so as to be vertically slidable such that the turntable 103
is sandwiched between the upper and lower punch holding portions
104 and 105. On the turntable 103, there is a die portion made up
of a plurality of die mounting holes 106, for fitting the die 114
so as to be detachable/reattachable, that are provided along the
same circumference. On each of the upper and lower punch holding
portions 104 and 105, there are a plurality of punch holding holes
107 drilled respectively for holding the upper and lower punches so
as to be slidable. Each of the die mounting holes 107 and the punch
holding holes 106 is drilled on the turntable such that the lower
punch 108, the upper punch 109 and the die 114 are arranged
vertically with their center lines aligned. Rails 110 are provided
correspondingly for rail contact portions of the upper and lower
punches 109 and 108, and the punches move vertically on the rails
as they engage with and are guided by respective cams, which will
be discussed later. The die 114 has a die hole 113 cut vertically
through the die into which the tips of the upper and lower punches
109 and 108 are inserted. It should be noted that 112 represents a
compression roller while 115 a hopper in FIG. 4.
[0064] In addition to shaft-driven rotary compression molding
machine, there are other types thereof such as external gear-driven
(external gear type) and internal gear-driven (internal gear type)
rotary compression molding machines in which rotational drive force
is transmitted by equipping the turntable with a gear.
[0065] Next, a description will be given of the double-structured
punch used in the present invention and the portions associated
therewith.
[0066] The double punch used in the present invention has a core
punch and an outer punch enclosing part or whole of the outer
perimeter of the core punch, with the outer shape of the outer
punch being approximately identical to the inner shape of a die
except for those portions where the core punch is not enclosed by
the outer punch. Further, both the core and outer punches are
slidable and manipulatable for compression operation. Here, the
core and outer punches are basically slidable independently of each
other, except for those portions that slide by coordination of the
two punches. It should be noted that a single core punch is
branched at the tip rather than having independent punches. Such a
punch is preferred because it is possible to make the amount of
pressure transferred and the pressure transfer speed the same
during compression in order to maintain the same moldability for a
plurality of cores. Further, the punch is also advantageous in
terms of punch manufacture and operation because it does not result
in a complicated form due to its structure. It is also possible to
use, for the punch, an integrally structured shell portion separate
from the tip portions all of which can be integrated into one piece
by fastening them. Although not preferred, it is possible to use a
plurality of independent core punches rather than branch the tip of
a single core punch.
[0067] As specific examples of punch tips, the shapes shown in
FIGS. 1 and 9 reflect the tip shapes as is, however, when viewed in
this manner the shaded areas represent the core punch and the
remaining areas correspond to the outer punch. To provide a scored
line at the division surface on the molded products in FIG. 9, a
scored line in the form of a concave recess can be formed on the
molded product surface by using a punch provided with a convex line
on the punch surface. It should be noted that a scored line can be
provided on either the upper or lower punch or both thereof.
[0068] An example of punch can be exemplified by a punch having a
structure as shown in FIG. 7, which corresponds to the punch shown
in FIG. 6. This punch has the core and outer punches 5A and 5B, an
outer punch compression head 78, a core punch compression head 79
and an outer punch vertical sliding motion adjustment roller 73. In
the compression molding step, compression of the core portions is
carried out mainly by pressing the core punch compression head 79
with compression rollers (45, 47, 49, 51 in FIG. 6) whereas
compression of the portions other than the core portions is
performed by pressing the outer punch compression head 78 with
compression rollers (68, 70 in FIG. 6). This allows for compression
operation using the core and outer punches.
[0069] While the vertical sliding motion of the core punch is
controlled by a normal method mainly using the core punch rail and
a core bottom portion 37 (same portion as the core punch
compression head 79), the vertical sliding motion adjustment roller
73 is provided that comes in direct contact with the outer punch
rail to allow vertical sliding motion of the outer punch.
Preferably, a plurality of bearings 77 are provided within the
rollers to allow rotation of the rollers and smooth vertical
sliding motion of the outer punch.
[0070] Here, the vertical sliding motion adjustment roller 73 is
arranged outside the outer punch compression head 78, with the
vertical sliding motion adjustment roller 73 separated from the
outer punch compression head 78. This allows the compression roller
to apply pressure only to the outer punch compression head 78 while
not applying direct pressure to the vertical sliding motion
adjustment roller 73, thus preventing damage to the bearings 77
within the vertical sliding motion adjustment roller 73. In
compression operation, it is possible to apply pressure to the
outer punch more from the side of the core punch, thus allowing
efficient transfer of pressure from the compression roller to the
powder or granular particles. Contact portions of the compression
rollers of the core and outer punches (the outer punch compression
head 78 and the core punch compression head 79) are vertically
separated from each other, thus preventing interference between the
compression rollers of the core and outer punches.
[0071] While FIG. 7 assume the lower punch, the same holds true for
the upper punch. Among differences between the upper and lower
punches are a shorter length of the tip portion of the upper punch
inserted into the die and different portions prescribing the punch
motion (e.g., spaces within the punches) due to difference in
motion between the upper and lower punches.
[0072] Alternatively, the double punch used in the present
invention may be that in which the motions of the core and outer
punches are respectively controlled in reverse. That is, the punch
controls the motion of the core punch with the vertical sliding
motion adjustment roller and the rail and the motion of the outer
punch with the punch bottom portion and the rail. A description of
the punch will be omitted since the same holds true for the punch
as for the punch of FIG. 7, except that the motions of the core and
outer punches are respectively controlled in reverse.
[0073] Next, a description will be given in detail of an embodiment
of the apparatus corresponding to the manufacturing method (FIG. 2)
together with operations of the portions thereof mainly with
reference to FIGS. 5 and 6 and, as necessary, FIG. 2 as the
apparatus for manufacturing the controlled release molded product
of the present invention that is the rotary compression molding
machine.
[0074] When viewed from above the turntable, the powder or granular
particles supply portions 8, 9 and 10, powder or granular particles
charging portions 11, 12 and 13, powder or granular particles
rubbing-cutting portions 14, 15 and 16, compression molding
portions 17, 18, 19 and 20, residual powder or granular particles
removal portions 21 and 22 and a product unloading portion 23 are
provided along the direction of rotation of a turntable 1 as shown
in FIG. 5.
[0075] Description will be made on a mechanism-by-mechanism basis.
The powder or granular particles supply portions (8, 9, 10 in FIG.
5) can be separated, according to the sequence of supply of powder
or granular particles, into the portion 8 for supplying the powder
or granular particles for the first outer layer OP1, the portion 9
for supplying the powder or granular particles for the cores NP and
the portion 10 for supplying the powder or granular particles for
the second outer layer OP2, with the powder or granular particles
supplied by natural fall or by a metered supply machine (not shown)
from hoppers 24, 25 and 26 filled with the respective powder or
granular particles.
[0076] The respective powder or granular particles supplied by the
powder or granular particles supply portions are sent next to the
powder or granular particles charging portions (11, 12, 13 in FIG.
5). The powder or granular particles charging portions are designed
to charge each of the powder or granular particles for the first
outer layer OP1, the cores NP and the second outer layer OP2,
respectively into the first outer layer space 201, the core space
202 or the second outer layer space 203 (refer to FIG. 2). These
portions are intended to hold fixed amounts of the respective
powder or granular particles supplied from the powder or granular
particles supply portions using open feed shoes 27, 28 and 29,
provided on the turntable 1 and capable of both storing and
supplying the powder or granular particles, and introduce each of
the powder or granular particles held by the feed shoes 27, 28 and
29 into the first outer layer space 201, the core space 202 or the
second outer layer space 203 (refer to FIG. 2) by lowering the
lower core punch 5A using lowerers 30, 31 and 32 provided on a
frame 34, and in certain circumstances, by lowering the lower outer
punch 5B using a lowerer 33 provided on a lower outer punch rail
36.
[0077] In detail, the powder or granular particles for the first
outer layer OP1 is charged by lowering the lower core and outer
punches 5A and 5B within the first open feed shoe 27 on the
turntable 1 (FIG. 2A). Here, with the lower core and outer punches
5A and 5B lowered, the lower outer punch 5B is maintained at a
constant height with respect to the turntable by moving the lower
outer punch 5B, during charging of the powder or granular particles
for the first outer layer OP1 or thereafter, along the lower outer
punch rail 36 installed so as to bring the extreme tip portion of
the lower outer punch 5B to the same height as the surface of the
turntable 1 using the vertical sliding motion adjustment roller 73
of the lower outer punch (FIG. 2B). On the other hand, the lower
core punch 5A is moved on a lower core punch rail 35 provided on
the frame 34 using the lower core punch bottom portion 37
(substantially the same portion as the core punch compression head
79 in FIG. 7) and further adjusted to a predetermined position
using the first core punch lowerer 30 provided on the lower core
punch rail 35. The powder or granular particles for the first outer
layer OP1 is thus introduced into the first outer layer space 201
roughly enclosed by the lower outer punch 5B and above the lower
core punch 5A.
[0078] Next, the powder or granular particles for the cores NP is
charged by raising the lower core punch 5A to a predetermined
height within the second open feed shoe 28 on the turntable 1 and
further moving the lower outer punch 5B on the lower outer punch
rail 36 installed so as to bring the extreme tip portion of the
lower outer punch 5B to the same height as the surface of the
turntable 1 using the vertical sliding motion adjustment roller 73
of the lower outer punch (FIGS. 2E to 2F). On the other hand, the
lower core punch 5A holding the temporary molded product of the
first outer layer on a lower core punch upper end surface 7A is
moved using the lower core punch bottom portion 37 on the lower
core punch rail 35 provided on the frame 34 and further lowered
using the second core punch lowerer 31 provided on the lower core
punch rail 35. The powder or granular particles for the cores NP is
thus introduced into the core space 202 roughly enclosed by the
lower outer punch 5B and above the temporary molded product of the
first outer layer.
[0079] Further, the powder or granular particles for the second
outer layer OP2 is charged by lowering both the lower core punch 5A
holding the temporarily molded first outer layer OP1 and cores NP
and the lower outer punch 5B or the lower outer punch 5B within the
third open feed shoe 29 on the turntable 1 (FIGS. 2I and 2J). Here,
the lower outer punch 5B is lowered using the lower outer punch
lowerer 33 provided on the lower outer punch rail 36. On the other
hand, the lower core punch 5A is moved using the lower core punch
bottom portion 37 on the lower core punch rail 35 provided on the
frame 34 and lowered using the third core punch lowerer 32 provided
on the lower core punch rail 35. The powder or granular particles
for the second outer layer OP2 is thus introduced into the second
outer layer space 203 created above and around the temporary molded
products of the first outer layer OP1 and the cores NP within the
die 3 by lowering both the lower core and outer punches 5A and 5B
or only the lower outer punch 5B.
[0080] Although the third open feed shoe 29 is shown larger than
the other open feed shoes in FIG. 6, this is intended to provide a
detailed description thereof. It should be noted that, in place of
the open feed shoes, agitation feed shoes may be employed that
forcefully charge the powder or granular particles into the die
using agitation vanes (installed at the same positions as the open
feed shoes; not shown).
[0081] The die and punches charged with the powder or granular
particles by the powder or granular particles charging portions
next enter the powder or granular particles rubbing-cutting
portions (14, 15, 16 in FIG. 5). The powder or granular particles
rubbing-cutting portions adjust the powder or granular particles
for the first outer layer OP1, the cores NP and the second outer
layer OP2 supplied and charged as described above to fixed amounts.
That is, the respective excess powder or granular particles
overflowing from the given spaces are rubbed and cut for removal by
rubbing-cutting plates 38, 39 and 40 as the lower core punch 5A or
both the lower core and outer punches 5A and 5B are raised to
predetermined positions by the lower outer and core punch rails 36
and 35.
[0082] In detail, the powder or granular particles for the first
outer layer OP1 is rubbed and cut by the rubbing-cutting plate 38
attached to the first open feed shoe 27 on the turntable 1. Here,
with the extreme tip portion of the lower outer punch 5B level with
the surface of the turntable 1, the lower core punch 5A is raised
to a predetermined position, thus causing the excess amount of the
powder or granular particles for the first outer layer OP1 charged
into the first outer layer space 201 to overflow from the space.
Further, the overflowing powder or granular particles for the first
outer layer OP1 is rubbed and cut by the rubbing-cutting plate 38
attached to the open feed shoe 27, thus leaving behind a fixed
amount of the charged powder or granular particles for the first
outer layer OP1 (prior to and following FIG. 2B).
[0083] Next, the powder or granular particles for the cores NP are
rubbed and cut by the rubbing-cutting plate 39 attached to the
second open feed shoe 28 on the turntable 1 as with the powder or
granular particles for the first outer layer. Here, with the
extreme tip portion of the lower outer punch 5B level with the
surface of the turntable 1, the lower core punch 5A is raised to a
predetermined position, thus causing the excess amount of the
powder or granular particles for the cores NP charged into the core
space 202 to overflow from the space. Further, the overflowing
powder or granular particles for the cores NP is rubbed and cut by
the rubbing-cutting plate 39 attached to the second open feed shoe
28, thus leaving behind a fixed amount of the charged powder or
granular particles for the cores NP (prior to and following FIG.
2F).
[0084] The powder or granular particles for the second outer layer
OP2 are also rubbed and cut by the rubbing-cutting plate 40
attached to the third open feed shoe 29 on the turntable 1 as with
the powder or granular particles for the first outer layer and the
cores. Here, the temporary molded products of the first outer layer
and the cores, held by the lower core and outer punches 5A and 5B,
are pushed up into the powder or granular particles for the second
outer layer OP2 supplied into the die 3 as the lower core punch 5A
or both the lower core and outer punches 5A and 5B are raised to
predetermined positions, thus causing the excess amount of the
powder or granular particles for the second outer layer OP2 to
overflow. Further, the overflowing powder or granular particles for
the second outer layer OP2 is rubbed and cut by the rubbing-cutting
plate 40 attached to the third open feed shoe 29, thus leaving
behind a fixed amount of the charged powder or granular particles
for the second outer layer OP2 (following FIG. 2K).
[0085] The die and punches charged with fixed amounts of the powder
or granular particles next enter the compression molding portions
(17, 18, 19, 20 in FIG. 5). The compression molding portions are
intended to perform precompression or main compression on one of
the powder or granular particles for the first outer layer OP1, the
cores NP and the second outer layer OP2 or a combination of two or
more thereof (including temporary molded products) using
compression rollers (44 to 51, 67 to 70) held by the frame 34.
[0086] In detail, temporary compression of the powder or granular
particles for the first outer layer OP1 or the temporary molded
product of the first outer layer OP1 and the powder or granular
particles for the cores NP is carried out by pressing using the
upper and lower core punches 4A and 5A. Here, the upper core punch
4A is lowered by upper core punch lowering cams 41 and 42 furnished
on an upper core punch rail 52, and preferably the upper outer
punch 4B is also concurrently lowered to a predetermined position
by upper outer punch lowering cams 53 and 54 furnished on an upper
outer punch rail 56, thus inserting the tip of the upper core punch
4A into the spaces above the lower core punch 5A and roughly
enclosed by the lower outer punch 5B within the die 3. The powder
or granular particles for the first outer layer OP1 charged into
the given space or the temporary molded product of the first outer
layer OP1 and the powder or granular particles for the cores NP are
thus confined from above and below and pressed so as to be
sandwiched between the upper temporary compression rollers 44 and
46 and the lower temporary compression rollers 45 and 47, thus
molding temporary molded products (FIGS. 2C and 2G). It should be
noted that although not preferred, it is possible to omit the
compression-molding portion for the powder or granular particles
for the first outer layer OP1 provided at the beginning.
[0087] Precompression (temporary compression) of the temporary
molded products of the first outer layer OP1 and the core NP and
the powder or granular particles for the second outer layer OP2 is
carried out by pressing using the upper core and outer punches 4A
and 4B (upper punch) and the lower core and outer punches 5A and 5B
(lower punch). To insert the upper core and outer punches 4A and 4B
into the die 3, the upper core and outer punches 4A and 4B are
lowered to predetermined positions using an upper core punch
lowering cam 43 furnished on the upper core punch rail 52 and an
upper outer punch lowering cam 55 furnished on the upper outer
punch rail 56, inserting the tips thereof into the die 3. The
temporary molded products of the first outer layer OP1 and the core
NP and the powder or granular particles for the second outer layer
OP2 are thus confined so as to be sandwiched from above and below
and press-molded in a preliminary fashion by the precompression
roller 48 for the upper core punch, the precompression roller 67
for the upper outer punch, a precompression roller 49 for the lower
core punch and the precompression roller 68 for the lower outer
punch.
[0088] In main compression following precompression (temporary
compression), the aforementioned molded product press-molded in a
preliminary fashion is press-molded as is in a full scale manner by
the main compression roller 50 for the upper core punch, the main
compression roller 69 for the upper outer punch, the main
compression roller 51 for the lower core punch and the main
compression roller 70 for the lower outer punch (FIG. 2M). It
should be noted that although not preferred, it is possible to use
only the present main compression portion by omitting the
precompression portion of the molded products of the first outer
layer OP1 and the core NP and the powder or granular particles for
the second outer layer OP2.
[0089] Next, the residual powder or granular particles removal
portions (21, 22 in FIG. 5) are provided at the precompression
portion of the powder or granular particles for the first outer
layer OP1 or the cores NP or a portion immediately thereafter. As
shown in FIG. 2, in the temporary compression step or immediately
thereafter, the lower outer punch 5B is held such that the extreme
tip portion thereof is maintained at the same height as the surface
of the turntable 1, and the powder or granular particles 57 for the
first outer layer OP1 or the powder or granular particles 58 for
the cores, remaining on the upper end surface 7B of the lower outer
punch is removed by suction and/or compressed air injection,
etc.
[0090] In detail, the upper end surface 7B of the lower outer punch
5B shown in FIG. 2 corresponds to the circumferential edge 76
(bevel angle) of the finished product shown in FIG. 3, and the
residual powder or granular particles 57 and 58 remain at the
portion. The residual powder or granular particles 57 and 58 are
impossible to remove by rubbing and cutting using the
rubbing-cutting plates 38 and 39 of the open feed shoes or
agitation feed shoes provided on the turntable 1 and, if left
unremoved, cause a concern over contamination between the powder or
granular particles for the first outer layer OP1 and the cores NP
and that between the powder or granular particles for the cores NP
and the second outer layer OP2. In the embodiment, for this reason,
the residual powder or granular particles 57 and 58 are removed by
the first and second residual powder or granular particles removal
portions 21 and 22 furnished on the turntable 1 following the
precompression step (FIGS. 2D and 2H). A residual powder or
granular particles removal mechanism constituting the residual
powder or granular particle removal portion comprises, for example
as shown in FIG. 8, compressed air injection nozzles 60 for
injecting compressed air onto the die surface from all directions
and suction boxes 75 and 61 provided with suction holes 59 for
aspirating the residual powder or granular particles, with the
compressed air injection nozzles 60 and the suction boxes 75 and 61
arranged on and parallel to the surface of the turntable 1 so as to
sandwich the die and the punches. The compressed air injection
nozzles 60 inject compressed air onto the punches and the die from
all directions and further the suction holes 59 near the die
surface aspirate the residual powder or granular particles 57 and
58, keeping the residual powder or granular particles from flying
outside for reliable removal thereof.
[0091] An alternative method of removing the residual powder or
granular particles is by raising the upper core punch 4A or the
upper core and outer punches 4A and 4B with the temporary molded
product held in the space inside the lower outer punch 5B and
aspirating the entire die from the upper end surface of the die
(from the direction perpendicular to the turntable), thus removing
the powder or granular particles for the first outer layer OP1 or
for the cores NP remaining on the upper end surface 7B of the lower
outer punch and/or the temporary molded product. It is mandatory in
this method that the temporary molded product not be drawn in by
suction, and temporary compression operation cannot be omitted from
the outer layer molding step and the outer layer/core molding step.
It should be noted that the present residual powder or granular
particle removal portions may be omitted under certain
circumstances. In particular, when a flat-surfaced molded product
is made, the outer punch surface is also flat, thus requiring no
residual powder or granular particle removal portions.
[0092] The final molded product is sent to the product-ejecting
portion (23 in FIG. 5) for ejection outside the molding apparatus.
The product eject-ejecting portion is designed to eject the product
using a scraper 71 that guides to a chute 72 by pushing up the
product as the lower core and outer punches 5A and 5B rise.
[0093] In detail, the upper core and outer punches 4A and 4B are
raised along the rising sloped surface by upper core and outer
punch raising cams 62 and 63, thus pulling the punch tips out of
the die 3. Further, using lower core and outer punch push-up rails
66 and 65, the lower core and outer punches 5A and 5B are pushed
up, thus completely pushing a molded product 64 out of the die 3.
Here, it is preferred for easy ejecting of the molded product that
the tip surface of the lower outer punch 5B be maintained at the
same level as the surface of the turntable 1 and that the lower
core punch 5A be pushed up slightly more upward than the tip
surface of the lower outer punch 5B (FIG. 2N). The molded product
64 that has been pushed out is scraped using the scraper 71 for
ejecting outside the turntable 1 and then guided into the chute 72
for retrieval of the product.
[0094] In the apparatus of the present invention shown in FIG. 6,
means for moving the core and outer punches refer to the rails (the
lower outer punch rail 36, the lower core punch rail 35, the upper
outer punch rail 56, the upper core punch rail 52), the lowerers
(the first core punch lowerer 30, the second core punch lowerer 31,
the third core punch lowerer 32, the lower outer punch lowerer 33),
the raising cams (the upper core and outer punch raising cams 62
and 63), the lowering cams (the upper core punch lowering cams 41,
42 and 43, the upper outer punch lowering cams 53, 54 and 55), the
push-up rails (the lower core and outer punch push-up rails 66 and
65), the vertical sliding motion adjustment rollers (the vertical
sliding motion adjustment rollers 73 and 74 of the lower and upper
outer punches), the core punch bottom portion 37 and the bearings
77. On the other hand, means for allowing manipulation of the core
and outer punches for compression operation refer to the
compression rollers (the upper temporary compression rollers 44 and
46, the lower temporary compression rollers 45 and 47, the
preliminary compression roller 48 for the upper core punch, the
preliminary compression roller 67 for the upper outer punch, the
precompression roller 49 for the lower core punch, the preliminary
compression roller 68 for the lower outer punch, the main
compression roller 50 for the upper core punch, the main
compression roller 69 for the upper outer punch, the main
compression roller 51 for the lower core punch, the main
compression roller 70 for the lower outer punch), and the outer
punch compression head 78 and the core punch compression head 79 as
shown in FIG. 7. It should be noted that these include not only
elements of the apparatus main body but also those of the
punches.
Embodiments
[0095] The controlled release molded product according to the
present invention will be described specifically below with
reference to the following embodiments.
TEST EXAMPLE 1
MANUFACTURING EXAMPLE 1
[0096] The punch used, a flat edge angle punch capable of pressing,
has a double structure consisting of a core punch whose three tip
portions, rectangular or square, are arranged roughly at 1
mm-intervals from the outside to the center portion and measure 2
mm.times.3 mm, 1 mm.times.3 mm and 1 mm.times.1 mm on each side,
and an outer punch of 10.0 mm in outer diameter enclosing the outer
perimeter of the core punch. A die provided with the aforementioned
punch above and below the die was used for the following
operations. Each punch surface was coated with a slight amount of
magnesium stearate (TAIHEI CHEMICAL INDUSTRIAL). With the lower
core punch lowered, 32 mg, 16 mg and 8 mg of hydroxypropylcellulose
(NIPPON SODA: HPC-L) were supplied into respective spaces enclosed
by the lower outer punch and above the lower core punch from
outside the molded product toward the center portion. By moving the
upper and lower core punches to engage each other, precompression
was manually conducted to such an extent that the surface became
flat. Next, with the lower core punch lowered, 8 mg, 4 mg and 2 mg
of thoeophyline (SHIZUOKA COFFEIN: "The Japanese Pharmacopoeia"
thoeophyline) were supplied into spaces above the temporary molded
products of hydroxypropylcellulose and enclosed by the lower outer
punch from outside toward the center portion. By moving the upper
and lower core punches to engage each other, temporary compression
was manually conducted similarly as previously done to such an
extent that the surface became flat. Further, with the lower punch
lowered, the remaining 352 mg of hydroxypropylcellulose was
supplied into a space above and around the molded products made up
of hydroxypropylcellulose and thoeophyline within the die such that
the temporary molded product of thoeophyline was completely covered
by hydroxypropylcellulose. Then, by moving the upper and lower
punches to engage each other, tabletting was conducted at a
compression pressure of about 0.5 tons--this time using a hydraulic
manual press (Shimadzu: SSP-10A). The tablet weight and hardness
were found to be 421 mg per tablet and 13 kg, respectively.
[0097] [Release Property Evaluation]
[0098] The molded product from manufacturing example 1 was
evaluated for release property in conformance with the Dissolution
Test of the General Tests, Processes and Apparatus of the Japanese
Pharmacopoeia, Thirteenth Edition. It should be noted that pure
water was used as test solution and that, to prevent the tablet
from adhering to the test vessel, the molded product was placed in
a Japanese Pharmacopoeia-compliant sinker for dissolution test. The
amount of thoeophyline eluted was calculated by measuring, with a
flow cell UV system (Shimadzu: UV-1600), the absorbance of given
amounts of the sampling solution using a dissolution tester (TOYAMA
CHEMICAL: NTR-6100A). The results are shown in FIG. 10.
[0099] It was discovered from FIG. 10 that there were three release
peaks at three and half, six and half and nine hours. Further, it
was found that, as compared with the first peak area, the second
and third peak areas declined. The reason for this lies in that
amount of thoeophyline released observed was proportional to the
amount of thoeophyline contained in the cores. It was determined
that the difference in core size (amount of thoeophyline added) was
reflected in the release property. Although thoeophyline
dissolution was observed in the interim period between cores, that
is, while filler dissolution was in progress over a time period in
the neighborhood of seven to eight hours after the start of
dissolution, this was thought to be caused by effective ingredient
diffusion through gel matrix because hydroxypropylcellulose, which
was used to form the gel matrix was used as filler in the present
test.
[0100] Thus, the inventor arrived at a molded product capable of
readily controlling not only time-dependent release but also
release amount by not providing multi-layer coating and by
adjusting core positions and shapes.
TEST EXAMPLE 2
[0101] While, in test example 1, a dissolution test was conducted
using pure water (dissolution test at pH near neutral), an
evaluation was performed next in test conditions assuming gastric
juice and intestinal conditions using a so-called enteric filler
(for example, Eudragit) that dissolves in the intestines rather
than in the stomach.
MANUFACTURING EXAMPLE 2
[0102] The punch used, a flat edge angle punch capable of pressing,
has a double structure consisting of a core punch whose three tip
portions of 1.5 mm in diameter are uniformly arranged (B-2 type in
FIG. 1) from the outside toward the center portion of the punch and
an outer punch of 10.0 mm in outer diameter enclosing the outer
perimeter of the core punch. A die provided with the aforementioned
punch above and below the die was used for the following
operations. Each punch surface was coated with a slight amount of
magnesium stearate (same as above). With the lower core punch
lowered, 20 mg each of Eudragit (Eudragit L100-55: HIGUCHI) was
supplied into respective spaces enclosed by the lower outer punch
and above the lower core punch, and by moving the upper and lower
core punches to engage each other, precompression was manually
conducted similarly to such an extent that the surface became flat.
Next, with the lower core punch lowered, 10 mg, 6 mg and 8 mg of
thoeophyline (same as above) were supplied into spaces above the
temporary molded products of Eudragit and enclosed by the lower
outer punch from the outer layer side toward the center portion. By
moving the upper and lower core punches to engage each other,
precompression was manually conducted similarly as previously done
to such an extent that the surface became flat. Further, with the
lower punch lowered, the remaining 320 mg of Eudragit was supplied
into a space above and around the molded products made up of
Eudragit and thoeophyline within the die such that the temporary
molded product of thoeophyline was completely covered by Eudragit.
Then, by moving the upper and lower punches to engage each other,
tabletting was conducted at a compression pressure of about 0.4
tons--this time using a hydraulic manual press (same as above). The
tablet weight and hardness were found to be 402 mg per tablet and
14 kg, respectively.
[0103] [Release Property Evaluation]
[0104] The molded product from manufacturing example 2 was
evaluated for release property in conformance with test example
1.
[0105] First, to evaluate the present preparation for dissolution
property in the acid region (assuming gastric juice condition), the
evaluation was conducted using a first solution (pH1.2) as the
dissolution test solution (not shown). As a result, absolutely no
dissolution was observed in the two-hour dissolution test using the
first solution, making evident that the present preparation had
sufficient resistance to gastric juice.
[0106] Next, to evaluate the dissolution property in the basic
region (assuming intestinal condition), the evaluation was
conducted using a second solution (pH6.8) as the dissolution test
solution (FIG. 11). As a result, it was discovered that there were
three release peaks at one and half, five and half and eight and
half hours. It was further confirmed from the difference in
magnitude between individual release peaks, release was
proportional to the amount of thoeophyline present in the
cores.
[0107] From the above, a molded product was successfully obtained
that is capable of releasing the effective ingredient at constant
intervals while having the function as enteric coating even in the
present preparation by direct tabletting as in the conventional
arts.
[0108] While detailed descriptions have been given of the
controlled release molded product of the present invention, the
technical scope of the present invention is not limited to the
aforementioned embodiments.
INDUSTRIAL APPLICABILITY
[0109] Unlike controlled release molded products made by
conventional intricate manufacturing methods such as multi-layer
coating, the present invention is a molded product in which
substantially a plurality of cores containing an effective
ingredient are localized, making it possible to mold the molded
product in a single step from powder or granular particles. This
not only ensures high production efficiency but also allows for the
cores to be arranged at specific positions, reducing to the minimal
possible level variations between finished molded products and
thereby allowing for manufacture of quality-assured highly accurate
molded products. Therefore, the present invention makes controlled
release molded products that are industrially viable in various
fields and is best suited notably to the field of pharmaceutical
drugs where accuracy is demanded of molded products.
* * * * *