U.S. patent application number 10/740225 was filed with the patent office on 2004-07-08 for two-part capsule to accept pharmaceutical preparations for powder inhalers.
This patent application is currently assigned to Boehringer Ingelheim Pharma KG. Invention is credited to Eckert, Josef, Hochrainer, Dieter.
Application Number | 20040131668 10/740225 |
Document ID | / |
Family ID | 7876530 |
Filed Date | 2004-07-08 |
United States Patent
Application |
20040131668 |
Kind Code |
A1 |
Hochrainer, Dieter ; et
al. |
July 8, 2004 |
Two-part capsule to accept pharmaceutical preparations for powder
inhalers
Abstract
The present invention relates to capsules for holding
pharmaceutical preparations for powder inhalers with increased drug
safety and capsules for pharmaceutical preparations for powder
inhalers with improved adaptation to their use in powder inhalers.
The capsules consist of water-insoluble hydrophobic synthetic
materials which do not significantly affect the pharmaceutical
quality of the contents themselves, but which improve the usability
of the filled capsules with regard to their function, their
longevity and/or the geographic location of their use, and are
advantageous at various stages from manufacture up to
utilisation.
Inventors: |
Hochrainer, Dieter;
(Schmallenberg, DE) ; Eckert, Josef;
(Mellrichstadt, DE) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877
US
|
Assignee: |
Boehringer Ingelheim Pharma
KG
Ingelheim
DE
|
Family ID: |
7876530 |
Appl. No.: |
10/740225 |
Filed: |
December 18, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10740225 |
Dec 18, 2003 |
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09800647 |
Mar 7, 2001 |
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09800647 |
Mar 7, 2001 |
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09365912 |
Aug 3, 1999 |
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60113214 |
Dec 22, 1998 |
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Current U.S.
Class: |
424/451 |
Current CPC
Class: |
A61M 15/0028 20130101;
A61M 15/003 20140204; A61J 3/071 20130101; A61M 2202/064 20130101;
A61K 9/4816 20130101; A61K 9/0075 20130101; A61J 3/072
20130101 |
Class at
Publication: |
424/451 |
International
Class: |
A61K 009/48 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 5, 1998 |
DE |
198 35 346.4 |
Claims
What is claimed is:
1. A capsule to hold a pharmaceutical preparation for powder
inhalation which comprises a capsule body and a capsule cap, which
are to be attached to one another so as to form a stable, enclosed
hollow space of defined volume, the capsule body and the capsule
cap being made of a water-insoluble, hydrophobic synthetic
material.
2. The capsule according to claim 1, characterized in that the
walls of the cap and the body are 0.1 mm to 0.5 mm thick.
3. The capsule according to claim 1, characterized in that the
capsule can withstand a force acting upon its longitudinal axis and
its transverse axis of up to 15 N.
4. The capsule According to claim 1, characterized in that the
Shore hardness D of the synthetic material is in the range from 65
to 73.
5. The capsule according to claim 1, characterized in that the wall
of the capsule has a steam permeability of less than
1.3.times.10.sup.-14 kg/(m.sup.2 s Pa).
6. The capsule according to claim 5, characterized in that the wall
of the capsule has a steam permeability of 1.5.times.10.sup.-16 to
2.times.10.sup.-16 kg/(m.sup.2 sPa).
7. The capsule according to claim 1, characterized in that the
synthetic material is polyethylene, polycarbonate, polyester,
polypropylene or polyethyleneterephthalate.
8. The capsule according to claim 7, characterized in that the
synthetic material is polyethylene with a density of 9,000-10,000
kg/m.sup.3.
9. The capsule according to claim 1, characterized in that one or
more elevations or recesses are located on the inner jacket of the
cap and one or more recesses or elevations are located on the outer
jacket of the body, these elevations or recesses being arranged so
that the elevations engage with the recesses when the capsule is
closed, by attaching the capsule body and the capsule cap.
10. The capsule according to claim 1, characterized in that a bulge
runs in an annular shape around the outside of the body
perpendicular to the connecting axis of the cap and the body, the
side of the bulge which is orientated towards the open end of the
body standing practically at right angles to the outer wall of the
body.
11. The Capsule according to claim 1, characterized in that the
capsule body and capsule cap are both made of high density
polyethylene and are both in the shape of a cylinder of round cross
section with a convex closed end, so that the elongation of the
capsule (distance from the closed end of the body to the closed end
of the cap in relation to the diameter when the capsule is closed)
is greater than 1.
12. The capsule according to claim 12, characterized in that the
joint between the body and cap, or the gap, is sealed by welding,
adhesive bonding, wrapping or covering the cap with a protective
film.
13. The capsule according to claims 12, characterized in that the
joint between the body and cap, or the gap, is sealed by filling
with a pharmaceutically acceptable filler.
14. The capsule according to claim 13, characterized in that the
filler is Eudragit.
15. The capsule according to claim 1 which further comprises in the
enclosed hollow space a pharmaceutical preparation comprising
cromoglycic acid, reproterol, beclomethasone, terbutaline,
albeterol, salmeterol, ketotifen, orciprenaline, fluticasone,
ipratropium, dexamethasone, bambuterol, tiotropium, budesonide,
fenoterol, clenbuterol, prednisolone, prednisone, prednylidene,
methylprednisolone, formoterol, nedocromil, insulin, ipratropium
bromide, tiotropium bromide, a salt thereof or a mixture thereof or
another cortisone preparation or atropine derivative, which
pharmaceutical preparation is suitable for inhalation.
Description
[0001] The invention relates to new two-part capsules for holding
pharmaceutical preparations for use in powder inhalers.
THE PRIOR ART
[0002] Capsules with pharmaceutical preparations are often used in
the therapy and diagnosis of illnesses. The capsules can be orally
administered or are used in certain medical apparatus such as
powder inhalers. Generally, the capsules consist of two parts, a
capsule body (body) and a capsule cap (cap), which are pushed
together telescopically. However, multi-part capsules are also
known. The capsules generally consist of gelatine, especially hard
gelatine. In the case of some special applications, the capsules
occasionally consist of water-soluble synthetic materials easily
digested by humans, in order for example to release the active
ingredients in certain compartments of the gastrointestinal tract
in the case of oral administration. Examples of various capsule
materials are listed hereinafter.
[0003] EP 0143524 discloses a two-part capsule of material which is
easily digestible by humans, preferably gelatine.
[0004] EP 0460921 describes capsules of chitosan and starch, grain
powder, oligosaccharides, methacrylic acid-methylacrylate,
methacrylic acid-ethylacrylate,
hydroxypropylmethylcelluloseacetate, succinate or phthaleate. The
capsule material is distinguished by the contents not being
released until they reach the large intestine.
[0005] GB 938828 discloses capsules for radioactive substances used
in therapy or diagnosis. The capsules comprise water-soluble
gelatine, methylcellulose, polyvinylalcohol or water-soluble
non-toxic thermoplasts.
[0006] The materials which are used are often not very resistant to
air humidity, which is why the pharmaceutical quality of the
contents cannot be guaranteed for all climatic zones. Especially in
climatic zone 4 (30.degree. C./70% relative air humidity),
conventional capsules cannot be used.
[0007] Two-part capsules, which are specially adapted for use in
powder inhalers without necessarily being subjected to the
conditions for oral administration, are previously not known in the
prior art. The capsules for powder inhalers comprise the same
materials as are used for oral administration, usually hard
gelatine. However, these materials are not specially perfected for
use in powder inhalers.
[0008] One of the objectives of the present invention is to provide
capsules which can be better adapted to the special conditions in
powder inhalers.
[0009] The capsules which have hitherto been used in powder
inhalers have various disadvantages as a result of their
composition. Hence materials used in construction of the capsules
can alter their characteristics dependent on the ambient air
humidity and/or do not always have sufficient inherent stability.
As a result, such a capsule cannot for example be used in climatic
zone 4 as a result of the high air humidity, since the capsule
material absorbs the humidity to such a degree that the inherent
stability is seriously affected and/or the humidity penetrates into
the interior of the capsule. This has a negative effect on the
pharmaceutical quality of the capsule's contents. The said
materials also have diverse disadvantages in other various stages
in the life of the capsule from manufacturing up to utilisation,
which affect the suitability of the capsule as a carrier for
pharmaceutical preparations, the manner of administration of the
contents, the perishability of the contents and/or the usability of
the capsule in certain countries. A further disadvantage of
conventional capsule materials is that e.g. they tend to bind
powder materials to themselves, especially when coated with a mould
release agent which is often necessary for production of the
capsule. In the case of capsules for inhalation purposes, this
leads to difficulty in accurately metering the fine fraction which
is to enter the lungs.
[0010] A further objective of the present invention is to provide
capsules for powder inhalers which do not have the aforementioned
problems of conventional capsules.
DESCRIPTION OF THE INVENTION
[0011] The present invention relates to a capsule for holding
pharmaceutical preparations for powder inhalers with increased drug
safety and capsules for pharmaceutical preparations for powder
inhalers with improved adaptation to use in powder inhalers. The
capsules consist of water-insoluble, hydrophobic synthetic
materials, which do not themselves substantially influence the
pharmaceutical quality of the contents, but which improve the
usability of the filled capsules with regard to their function,
their longevity and/or the climatic zone, and are advantageous at
various stages from production through to utilisation.
[0012] The capsules, according to the invention, consist of two
parts, a capsule body (body) and a capsule cap (cap), which can be
connected together so as to form a stable enclosed hollow space of
defined volume which contains the pharmaceutical formulation. The
dimensions of the capsule are chosen so that the capsule can be
used with common powder inhalers which are used with capsules, such
as those described for example in patent documents DE 33 45 722
(Inhaler Ingelheim M), EP 0 591 136 (Inhaler Ingelheim) or in the
published German application DE 43 18 455 ("HandiHaler.RTM.").
DETAILED DESCRIPTION OF THE INVENTION
[0013] In one embodiment, the synthetic material of the capsule is
not digestible by humans, so that the active ingredient is not
released when the capsule is taken orally. This has the advantage
that inadvertent swallowing of the capsule cannot lead to a
detrimental effect on health. This applies especially to small
children or older people.
[0014] Preferably, synthetic materials are used which can be
processed using injection moulding or blow casting and/or synthetic
materials where no mould release agent is necessary for their
processing into capsule caps or capsule bodies, which can cause
adhesion of the contents to the capsule wall. This has the
advantage that the interior of the cap or the body need not be
cleaned from mould separation agent, in order for example to meet
the official requirements (e.g. according to DAB (Deutsches
Apotheker Buch)), which restricts the use of mould release agents
for primary packaging means.
[0015] In a preferred embodiment of the invention, the synthetic
material does not exhibit any pronounced adhesion for
pharmaceutical-chemical materials, especially for particles of
lung-accessible size, so that when the capsule is used in one of
the aforementioned inhalers, the entire contents of the capsule can
be released. This has the advantage that exact dosage, especially
of the lung-accessible fine fraction, is possible.
[0016] In a further embodiment, the capsule consists of a synthetic
material with a Shore hardness D of 65 to 73. A synthetic material
of this hardness does not shatter when it is pierced or cut open,
but at the same time it is rigid enough so that the resulting hole
does not close up again. The advantage of such material is that no
fragments can be forced out of the capsule during opening, piercing
or slicing open of the capsule in the powder inhaler which can be
breathed in during inhalation.
[0017] In one embodiment, the synthetic material capsule is so
stable that it can withstand a force along its longitudinal axis or
transverse axis of up to 15 N. The advantage of this is that the
capsule is better adapted to the stress which acts upon it during
manufacture, filling, packaging, transportation and the like.
[0018] In a further embodiment, the wall of the capsule has a steam
permeability of less than 1.3.times.10.sup.-14 kg/(m.sup.2 s Pa),
preferably of 1.5.times.10.sup.-16 to 2.times.10.sup.-16
kg/(m.sup.2 s Pa). The advantage of this feature is that the
contents of the capsule are also protected from water in
geographical zones with high air humidity.
[0019] In preferred embodiments, the synthetic material is
polyethylene, especially polyethylene with a density of between
9000 and 10,000 kg/m.sup.3.sub.1 preferably 9600 kg/m.sup.3
(high-density polyethylene), polycarbonate, polyester,
polypropylene or polyethyleneterephthalate.
[0020] In a preferred embodiment, the cap and the body have the
shape of a cylinder with a round cross-section and a convex,
practically hemispherical closed underside, and both consist of
high-density polyethylene with a density of between 9500 and 10000
kg/m.sup.3.
[0021] The capsules according to the invention can be used in all
kinds of powder inhalers where the preparation which is to be
inhaled is administered by means of a capsule.
[0022] In a preferred embodiment, the cap and body of the capsule
are of mutually-similar cylindrical shape, comprising an inherently
closed jacket with, in each case, a closed end and an open end.
Here, the shape and size of the cap and the capsule are such that
the body can be pushed telescopically into the open end of the cap
with its open end, so that the cap is attached solidly to the
body.
[0023] In a special embodiment, the cap and body are provided with
locking devices, which are advantageous for temporary and/or final
closure of the capsule.
[0024] In such an embodiment, there are point-shaped elevations on
the inner jacket of the cap and on the outer jacket of the body
there are somewhat larger point-shaped recesses which are arranged
so that the elevations engage with the recesses on closure of the
capsule. Alternatively, the elevations can be located on the outer
jacket of the body and the recesses on the inner jacket of the cap.
Arrangements are preferred where the elevations or recesses are
respectively disposed in a ring or spiral shape about the jacket.
Instead of the point-shaped design of the elevations and recesses,
these can also run continuously around the cap or the body in a
ring-shape.
[0025] In one embodiment, one or more elevations, running annularly
around the inner jacket of the cap and the outer jacket of the
body, are designed so that elevations on the cap are each
positioned next to an elevation of the body when the capsule is
closed.
[0026] In embodiments with the aforementioned annular recesses
and/or elevations, these can be continuous or interrupted.
[0027] In a further embodiment, elevations are formed on the
outside of the body near the open end and holes are formed in the
cap near the open end so that the elevations of the body locate
into the holes in the cap when the capsule is closed. The
elevations can be designed so that the cap can be opened at any
time without damage to the capsule, or so that once closed, the
capsule can no longer be opened without being damaged.
[0028] In a further embodiment, a bulge is designed on the outer
side of the body, which runs around the body perpendicular to the
connecting axis between the cap and the body. The bulge serves as a
stopper for the capsule when this is placed over the body, in order
to prevent piercing of the cap with the body. The area between the
open end of the body and the bulge corresponds to the area of the
body over which the cap can be pushed. The bulge is located on the
body so that the cap can be pushed far enough over the body to
ensure good attachment between the cap and the body. That is, the
bulge may not, for example, be located directly on the open side of
the body. The side of the bulge which faces the open end of the
body stands as a vertical edge on the outer wall of the body so
that the cap cannot be pushed over the bulge on closure. The side
of the bulge which faces towards the closed end of the body can be
designed in the form of an almost right-angled edge or can taper
towards the closed end of the body. The formation of a practically
right-angled edge can be advantageous where the capsule fits
loosely into the capsule holder, whilst the version with the
tapering bulge can be advantageous in the case of a tight fit. The
bulge can be continuous or interrupted.
[0029] In a preferred embodiment, the bulge tapers continuously to
the closed end of the body and stands with its end oriented towards
the open end of the body perpendicularly on the capsule body. The
height of the edge thus formed is such that, in the closed position
of the capsule, the edge does not project beyond the cap, thus
providing a flat transition from the cap to the body.
[0030] The thickness of the walls of the cap and the body can vary
over the entire area. Thus, the wall thickness is generally greater
in the rounded areas of the cap or the body, or at that point in
the body where the bulge is formed, than in the areas where the
walls run straight. In one embodiment, the walls of the cap and the
body have a thickness of 0.1 to 0.5 mm.
[0031] In one possible embodiment, knobs are formed on the outside
of the capsule, and in another embodiment there are three or more
ribs, which run parallel to the longitudinal axis of the capsule.
The advantage of these devices is that the capsule can be removed
from a capsule holder e.g. as used in the aforementioned powder
inhalers, in such a way that it does not get damaged or break open.
The ribs or the knobs can run around the entire outside of the
capsule or may only cover a part thereof. Alternatively, they may
only be provided on the cap or only in the area of the body which
is visible from outside in its closed state. The ribs run parallel
to the longitudinal axis of the capsule and ensure that the capsule
is fixed vertically in the aforementioned capsule holder. In the
case of the capsule having a circular cross-section, the ribs are
preferably arranged so that the cross-section of the capsule does
not have rotational symmetry about its central axis. In such an
embodiment, the ribs may be provided only in the area of the body
which is visible when the capsule is closed. This embodiment
prevents the capsule jamming in a capsule holder. In an embodiment
without a bulge but with ribs on the part of the body which is
visible when the capsule is closed, the ribs are designed so that
the ends of the ribs which are orientated towards the open end of
the body perform the function of the bulge, namely to act as a
stopper for the cap, when the cap is attached to the body.
[0032] In a further embodiment, the jackets of the cap and the body
describe a hollow cylinder with a round, oval, triangular,
quadrilateral, hexagonal, octagonal or polygonal cross-section,
where the respective upper side is open and the underside is
closed. The closed underside can be flat or convex. The angled
embodiments have the advantage that they can for example be stored
in a more space-saving manner than the round embodiments.
[0033] In one embodiment, the elongation of the capsule (distance
from the closed end of the body to the closed end of the cap in
relation to the diameter when the capsule is closed) is greater
than 1, in one embodiment the elongation is 1 and in yet another
embodiment the elongation is smaller than 1. The latter has the
advantage that the body has a larger opening for filling.
[0034] In one of the embodiments with an elongation of 1, the cap
and the body are designed so that the closed capsule is spherical,
which can be advantageous for automatic loading of a powder inhaler
with the capsule from a reservoir.
[0035] In order to attain better sealing between the cap and the
body when the filled capsules are closed, the joint between the cap
and the body can be welded, adhesively bonded or wrapped, thus
reducing the steam permeability to as little as a tenth.
Alternatively, the entire cap can be covered with a protective
film.
[0036] In another preferred embodiment, the gap may be sealed with
a filler. Suitable fillers for filling the gap in this way are the
pharmaceutically acceptable fillers such as Eudragit. A filler of
this kind can be inserted in the gap as a solution or suspension in
a suitable, preferably highly volatile solvent. Suitable solvents
include fluorochlorohydrocarbons such as methylene chloride or
chloroform, fluorohydrocarbons, alcohols such as methanol, ethanol,
propanol, isopropanol, alkanes such as propane, hexane, heptane,
ketones such as acetone, esters such as ethyl acetate, ethers such
as dimethylether or diethylether or other liquids known from the
prior art to be suitable for solutions or suspensions, especially
volatile liquids and those which do not attack the capsule
material, do not interact chemically with pharmaceutical
compositions or alter their bioavailability. The solution or
suspension with the filler must be of a nature and concentration
such that the solution or suspension delivers sufficient filler
into the gap so that, after the solvent has evaporated, the filler
left behind provides a tight seal and at the same time the solution
or suspension should not be of a nature and concentration such that
it is too viscous to penetrate into the gap or be drawn into it by
capillary action.
[0037] Preferably, a solution of Eudragit and acetone is used to
seal the gap.
[0038] It can be seen from the description that the capsule,
according to the invention, is suitable for holding any kind of
powdered pharmaceutical preparation which is suitable for
inhalation. In a special application, the capsule contains
cromoglycic acid, reproterol, beclomethasone, terbutaline,
salbutamol, salmeterol, ketotifen, orciprenaline, fluticasone,
insulin, ipratropium, dexamethasone, bambuterol, tiotropium,
budesonide, fenoterol, clenbuterol, prednisolone, prednisone,
prednylidene, methylprednisolone, formoterol, nedocromil, the salts
or mixtures thereof or another cortisone preparation or atropine
derivative suitable for inhalation purposes.
[0039] In a preferred embodiment, the capsule contains ipratropium
bromide or tiotropium bromide.
DESCRIPTION OF THE DIAGRAMS
[0040] The diagrams show various embodiments of the capsule
according to the invention by way of example, but only serve to
illustrate the invention without restricting its scope.
[0041] FIG. 1 shows the simplest embodiment of the capsules
according to the invention in lateral cross-section
[0042] FIGS. 2a and 2b each show a different embodiment of the
capsule with a tapering bulge on the body in lateral
cross-section
[0043] FIG. 3 shows an embodiment of the capsule with an angular
bulge on the body in lateral cross-section
[0044] FIG. 4 shows an embodiment of the capsule with a tapering
bulge on the body and annular recess on the body and cap in lateral
cross-section
[0045] FIG. 5 shows an embodiment of the capsule with tapering
bulge on the body and annular recess on the body and cap in frontal
view
[0046] FIG. 6 shows an embodiment of the capsule with tapering
bulge on the body and point-shaped recesses or elevations on the
body and cap in frontal view
[0047] FIG. 7 shows an embodiment of the capsule with tapering
bulge on the body and point-shaped elevations on the body and
point-shaped holes in the cap in frontal view
[0048] FIG. 8 shows an embodiment of the capsule with ribs on the
body in frontal view
[0049] FIG. 9 shows the capsule of FIG. 7 in horizontal
cross-section
[0050] FIGS. 10a, 10b and 10c show embodiments of the capsule, each
with a different cross-section.
[0051] An embodiment illustrating a spherical capsule is not
shown.
[0052] In FIG. 1, the simplest embodiment of the capsule according
to the invention 1 is shown in cross-section. The capsule 1
consists of the cap 2 and the body 3, which are fitted
telescopically one into the other. The cap 2 and the body 3 are of
the same shape and each has a convex underside 4.
[0053] FIG. 2a shows a cross-section of an embodiment where a bulge
5 is formed on the body 3 of the capsule 1, this bulge tapering
towards the closed end of the body. The bulge 5 stands practically
vertically on the body with its side orientated towards the open
end of the body. The edge thus formed demarcates the area of the
body over which the cap 2 can be pushed telescopically.
[0054] Another embodiment is shown in FIG. 2b. The cross-section
shows that this embodiment differs from that shown in FIG. 2a in
that the wall thickness of the cap 2 or the body 3 is not uniformly
great over the entire area, but rather varies over individual
partial areas. In addition, the convex undersides 4 of the cap or
the body each have a concave indentation at the vertex.
[0055] In FIG. 3 an embodiment is represented where the bulge 5
sits on the body almost at right angles to the upper side of the
body and also the underside of the body. The embodiment of FIG. 4
represents a further development of the embodiment of FIG. 2a,
where an annular recess 6 or 7 is formed in cap 2 or body 3 in
order to close the capsule 1 more satisfactorily.
[0056] FIG. 5 shows a front view of the embodiment shown in FIG. 4
as a cross-section.
[0057] FIG. 6 shows a further variant of the invention with
point-shaped recesses 8 and 9 in front view.
[0058] In FIG. 7, a variant of the capsule 1 is shown where
elevations 10 are provided on the body 3 near the open end, and
holes 11 are provided in the cap 2 near the open end so that the
elevations 10 engage with the holes 11 when the capsule is
closed.
[0059] FIG. 8 shows an embodiment of the capsule 1 from outside,
where ribs 12 are provided on the body 3.
[0060] FIG. 9 shows the body 3 of the embodiment in FIG. 7 in
cross-section. The cross-section shows that the three ribs 12 are
not arranged with rotational symmetry about the central axis of the
body. FIGS. 10a, 10b and 10c show a capsule 1 of quadrilateral,
triangular and octagonal cross-section, respectively.
* * * * *