U.S. patent application number 14/094699 was filed with the patent office on 2014-03-27 for hydroxypropyl methyl cellulose hard capsules and process of manufacture.
This patent application is currently assigned to CAPSUGEL BELGIUM NV. The applicant listed for this patent is CAPSUGEL BELGIUM NV. Invention is credited to Dominique Nicolas Cade, David He Xiongwei.
Application Number | 20140088202 14/094699 |
Document ID | / |
Family ID | 39144361 |
Filed Date | 2014-03-27 |
United States Patent
Application |
20140088202 |
Kind Code |
A1 |
Cade; Dominique Nicolas ; et
al. |
March 27, 2014 |
Hydroxypropyl Methyl Cellulose Hard Capsules and Process of
Manufacture
Abstract
A composition for manufacture of hard hydroxypropyl methyl
cellulose capsules comprising a film forming material of
hydroxypropyl methyl cellulose having a methoxy content of
27.0-30.0% (w/w), and a hydroxypropoxy content of 4.0-7.5% and as a
2% weight solution, a viscosity of 3.5-6.0 cPs at 20.degree. C.,
dipping compositions, process for manufacture of hard hydroxypropyl
methyl cellulose capsules according to a dip coating process and
hard capsule shells.
Inventors: |
Cade; Dominique Nicolas;
(Colmar, FR) ; He Xiongwei; David; (Andolsheim,
FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CAPSUGEL BELGIUM NV |
Bornem |
|
BE |
|
|
Assignee: |
CAPSUGEL BELGIUM NV
Bornem
BE
|
Family ID: |
39144361 |
Appl. No.: |
14/094699 |
Filed: |
December 2, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12446624 |
Feb 25, 2010 |
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PCT/IB07/03160 |
Oct 17, 2007 |
|
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14094699 |
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60863190 |
Oct 27, 2006 |
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Current U.S.
Class: |
514/780 ;
514/781 |
Current CPC
Class: |
A61J 3/077 20130101;
A61K 9/4833 20130101; A61K 9/0075 20130101; C08L 1/284 20130101;
A61K 9/4816 20130101; C08L 1/14 20130101 |
Class at
Publication: |
514/780 ;
514/781 |
International
Class: |
A61K 9/48 20060101
A61K009/48 |
Claims
1. An aqueous composition for manufacture of hard capsules,
comprising, in an aqueous solvent, 15-25% by weight, based on the
total weight of the aqueous composition, of a hydroxypropyl methyl
cellulose 2906 (HPMC 2906) having a methoxy content of 27.0-30.0%
(w/w), a hydroxypropoxy content of 4.0-7.5% (w/w) and a viscosity
of 3.5-6.0 cPs as a 2% weight solution in water at 20.degree. C.,
and less than 1% of a gelling system selected from (i) the group
consisting of at least one cation selected from the group
consisting of K+, Na+, Li+, NH4.sup.+, Ca.sup.++, Mg.sup.++ and
mixtures thereof and (ii) at least one gelling agent selected from
the group consisting of alginates, agar gum, guar gum, locust bean
gum (carob), carrageenan, tara gum, gum Arabic, ghatti gum, khaya
grandifolia gum, tragancanth gum, karaya gum, pectin, arabian
(araban), xanthan, gellan gum, konjac mannan, galactomannan,
funoran, and mixtures thereof.
2. The composition according to claim 1, wherein the hydroxypropyl
methyl cellulose has a viscosity of 4.0-5.0 cPs as a 2% weight
solution in water at 20.degree. C.
3. The composition according to claim 1, wherein 17-23% by weight
based on the total weight of the aqueous composition, is
hydroxypropyl methyl cellulose.
4. The composition according to claim 1, wherein the aqueous
solvent is water.
5-13. (canceled)
14. A hydroxypropyl methyl cellulose hard capsule shell containing
a hydroxypropyl methyl cellulose having a methoxy content of
27.0-30.0% (w/w), a hydroxypropoxy content of 4.0-7.5% (w/w) and a
viscosity of 3.5-6.0 cPs as a 2% weight solution in water at
20.degree. C. which is HPMC 2906 in an amount ranging from 70% to
90% by weight of the shell weight.
15-17. (canceled)
18. The composition according to claim 1, wherein the composition
contains 0% of the gelling system.
19. The composition according to claim 1, wherein for a
concentration of HPMC of 19% (w/w) in water, the composition has a
gelling temperature ranging from 30.degree. C. to 40.degree. C.
20. The capsule shell according to claim 14 wherein the
transmittance measured by UV at 650 nm on the capsule body is 80%.
Description
[0001] The present invention relates to an aqueous composition for
the manufacture of hydroxypropyl methyl cellulose (hereinafter also
"HPMC") hard capsules, a method of preparing HPMC hard capsules and
hard capsules obtained therewith.
[0002] Capsules are well-known dosage forms that normally consist
of a shell filled with one or more specific substances. The shell
may be a soft or, as in this invention, a hard stable shell
comprising film-forming polymer(s) such as gelatine, modified
starches, modified celluloses etc.
[0003] Hard capsules are generally manufactured by using a dip
molding process. In this process, pin molds are dipped into a film
forming composition. By gelling the film forming polymer on the
pin, a film is formed that is subsequently dried on the pin, to
obtain a capsule shells. The shells are then stripped of the pins
and cut to a desired length. Thus, capsules caps and bodies are
obtained that can later be filled with a substance and joined such
that a filled capsule is obtained.
[0004] When using this type of dip molding process, it is necessary
to ensure that the dipping composition adheres to the pin surface
and quickly gels, once the pins are withdrawn from the dipping
bath. This avoids that the composition flows on the pins surface so
as to achieve the desired shell or film distribution to manufacture
capsules.
[0005] When using gelatine as the film forming polymer, the dipping
compositions gel with cooling. The same gelling behaviour is shown
by mixtures of methyl celluloses and gelling agents. Both these
types of film forming polymers may be processed on conventional
devices for manufacturing hard gelatine capsules.
[0006] U.S. Pat. No. 2,526,683 discloses a process for preparing
methyl cellulose medicinal capsules by a dip coating process. The
process consists of dipping a capsule forming pin pre-heated to
40.degree. C.-85.degree. C. into a methyl cellulose composition
maintained at a temperature below the temperature where gelation
begins, withdrawing the pins and placing the pins in ovens at
temperatures above the gelation temperature and drying the film.
When the hot pins are dipped into the composition, the composition
gels on the surface of the pin and as the pin is withdrawn, a film
of gelled liquid of a certain thickness is formed on the pin. The
pin is then generally turned 180.degree. to an upright position and
typically placed in the oven to dry. This technique is
conventionally named "thermogelation". The dry capsule is then
stripped, cut to size and the body and caps are fitted together.
However, methyl cellulose is insoluble in water under 37.degree.
C.
[0007] U.S. Pat. No. 3,493,407, discloses the use of non-thermal
gelling dip-molding compositions of some hydroxyalkylmethyl
cellulose ethers in aqueous solvents. The pins must be kept in
rotation for more than half an hour to obtain capsules with a
regular shape.
[0008] U.S. Pat. No. 3,617,588, discloses the use of an induction
heater to gel cellulose ether.
[0009] U.S. Pat. No. 4,001,211 discloses improved thermogeling
compositions based on a blend of methyl cellulose and hydroxypropyl
methyl cellulose.
[0010] The compositions and processes described above did not make
it possible to obtain high-performance manufacturing of hard
capsules both with regard to speed, dissolution properties and with
regard to overall quality. Similarly, capsules manufactured by
combination of HPMC with gelling agents have very poor visual
quality and dissolution properties since they are sensitive to
cations and to pH.
[0011] Research is still going on into compositions with even
better qualities, particularly as regards the absence of defect,
the visual aspect, high performance on filling machines, good
dissolution properties and limited consumption of energy. Additives
should be avoided as much as possible.
[0012] It is an object of the instant invention to provide new
compositions particularly for the manufacture of HPMC capsules of
high quality: e.g. standardized dimension, high transparency
(similar to hard gelatine capsules), and excellent dissolution and
mechanical performance.
[0013] This and other objects are achieved by a first aspect of the
present invention which is an aqueous composition for the
manufacture of hard capsules, wherein the composition comprises, in
an aqueous solvent, 15-25% by weight, based on the total weight of
the aqueous composition, of a hydroxypropyl methyl cellulose having
a methoxy content of 27.0-30.0% (w/w), a hydroxypropoxy content of
4.0-7.5% (w/w) and a viscosity of 3.5-6.0 cPs as a 2% weight
solution in water at 20.degree. C.
[0014] In the present invention the HPMC methoxy and hydroxypropoxy
contents are expressed according to the USP30-NF25.
[0015] In the present invention the viscosity of the HPMC 2% weight
solution in water at 20.degree. C. is measured according to the
USP30-NF25 method for cellulose derivatives.
[0016] Preferably the aqueous composition comprises 17-23% by
weight, based on the total weight of the aqueous composition, of
the hydroxypropyl methyl cellulose.
[0017] Suitable hydroxypropyl methyl celluloses are commercially
available. For example suitable types are all those fulfilling the
requirements set forth in USP30-NF25 for HPMC type 2906.
[0018] Suitable aqueous compositions can be obtained by blending
HPMCs of same type but different viscosity grade.
[0019] In a preferred embodiment, the HPMC in the aqueous
composition of the invention is a HPMC having a viscosity of
4.0-5.0 cPs as a 2% w/w solution in water at 20.degree. C.
[0020] Viscosity of the HPMC solution in water can be measured by
conventional techniques, e.g. as disclosed in the USP by using a
viscometer of the Ubbelohde type.
[0021] In an embodiment, the aqueous compositions of the invention
may contain between 0% and 5%, preferably between 0% and 2% by
weight based on the total weight of the aqueous composition of
additional non animal-derived film-forming polymers typically used
for the manufacture of hard capsules. Preferably, the HPMC aqueous
compositions of the invention contain no other film-forming polymer
beside the HPMC presently disclosed. Non animal-derived
film-forming polymers are for example polyvinyl alcohol,
plant-derived or bacterial-derived film-forming polymers. Typical
plant-derived film-forming polymers are starch, starch derivatives,
cellulose, celluloses derivatives other than the HPMC as defined
herein and mixtures thereof. Typical bacterial-derived film-forming
polymer are exo-polysaccharides. Typical exo-polysaccharides are
xanthan, acetan, gellan, welan, rhamsan, furcelleran,
succinoglycan, scleroglycan, schizophyllan, tamarind gum, curdlan,
pullulan, dextran and mixtures thereof.
[0022] In a preferred embodiment, the HPMC aqueous compositions of
the invention contain between 0% and 1%, preferably 0% by weight
based on the total weight of the aqueous composition of
animal-derived materials conventionally used for the manufacture of
hard capsules. A typical animal-derived material is gelatin.
[0023] In a preferred embodiment, the aqueous compositions of the
invention contain less between 0% and 1%, preferably 0% by weight
based on the total weight of the aqueous composition of a gelling
system. By "gelling systems" it is meant one or more cations and/or
one or more gelling agents. Typical cations are K.sup.+, Na.sup.+,
Li.sup.+, NH.sub.4.sup.+, Ca.sup.++, Mg.sup.++ and mixtures
thereof. Typical gelling agent(s) are hydrocolloids such as
alginates, agar gum, guar gum, locust bean gum (carob),
carrageenans, tara gum, gum arabic, ghatti gum, khaya grandifolia
gum, tragacanth gum, karaya gum, pectin, arabian (araban), xanthan,
gellan gum, konjac mannan, galactomannan, funoran, and mixtures
thereof. As usually, gelling agents can optionally be used in
combination with cations and other ingredients such as sequestering
agents.
[0024] As the HPMC aqueous compositions disclosed herein are
suitable to give strong and physically stable gels without gelling
systems, the dissolution properties of the HPMC capsules of the
invention are not affected by the drawbacks typically associated
with gelling systems, notably cations.
[0025] At the natural state--i.e. without the addition of pigments
or similar ingredients in the composition--the HPMC hard capsules
obtainable from the aqueous compositions of the invention show good
clarity and transparency. The transmittance measured by UV at 650
nm on the capsule body (through its double shell layers) is around
80%, identical to gelatine hard capsules.
[0026] For obtaining coloured capsules at least one inert non-toxic
pharmaceutical grade or food grade pigment such as titanium dioxide
can be incorporated in the aqueous compositions. Generally, 0.001
to 1.0% by weight of pigment can be included in the aqueous
composition. The weight is expressed over the total weight of the
composition.
[0027] Optionally, an appropriate plasticizer such as glycerine or
propylene glycol can be included in the aqueous solutions. To avoid
an excessive softness, the plasticizer content has to be low, such
as between 0% and 2%, more preferably between 0% and 1% by weight
over the total weight of the composition.
[0028] The aqueous compositions of the invention can be prepared by
dispersing the HPMC and the other optional ingredients in one or
more aqueous solvents, preferably water. The aqueous solvent can be
at a temperature above room temperature, preferably above
60.degree. C., more preferably above 70.degree. C. Optimal
temperatures can be determined by the skilled person. In a
preferred embodiment after de-bubbling, the dispersion is cooled
down below room temperature, preferably below 15.degree. C., to
achieve the solubilisation of the HPMC.
[0029] The gelling temperature of the aqueous compositions may be
determined by a measurement of the viscosity by progressively
heating the composition. The temperature at which the viscosity
starts to sharply increase is considered as the gelling
temperature. As an example, for a concentration of about 19% w/w in
water, any HPMC of the invention fulfilling the USP definition of
HPMC type 2906 has a gelling temperature of about between 30 and
40.degree. C. As an additional example, for concentrations between
15 and 25% w/w in water, an HPMC of the invention fulfilling the
USP definition of HPMC with a hydroxypropoxy content of about 6%,
has a gelling temperature between about 30 and 40.degree. C. An
example of how gelling temperature can easily be measured is
provided in the examples.
[0030] The aqueous compositions of the invention can be used as
dipping compositions in dip-molding processes for the manufacture
of HPMC hard capsules.
[0031] It has been noted that the aqueous compositions of the
invention allow the manufacture of good HPMC hard capsules showing
optimal dissolution properties. Dissolution profile is a key point
in therapy to obtain a complete and reproducible release of the
substance contained in the capsule.
[0032] Additionally, it has been noted that the aqueous
compositions of the invention allow the manufacture of good HPMC
hard capsules whose bodies and caps, once telescopically joined,
can suitably be sealed. This makes the presently disclosed new HPMC
hard capsules a particularly good and cost-effective solution for
the manufacture of liquid-filled oral dosage forms as well as
powder-filled dosage forms for inhalation or the manufacture of
tamper-proof pharmaceutical forms to be used in the context of
double-blind trials.
[0033] In a second aspect, the present invention relates to a
process for the manufacture of hydroxypropyl methyl cellulose hard
capsules according to a dip coating process, characterized in that
it comprises the steps of:
(a) providing an aqueous composition of a hydroxypropyl methyl
cellulose having a methoxy content of 27.0-30.0% (w/w), a
hydroxypropoxy content of 4.0-7.5% (w/w) and a viscosity of 3.5-6.0
cPs as a 2% weight solution in water at 20.degree. C., wherein the
concentration of the hydroxypropyl methyl cellulose in the aqueous
composition is chosen to obtain a viscosity of the aqueous
composition of 1000 to 3000 cPs, preferably 1200 to 2500 cPs, more
preferably 1600 to 2000 cPs, measured at a temperature of
10.degree. C. to 1.0.degree. C. below the aqueous composition
gelling temperature, (b) pre-heating dipping pins so that they are
at 55-95.degree. C. when dipped into the aqueous composition, (c)
dipping the pre-heated dipping pins into the aqueous composition
maintained at a temperature of 10.degree. C. to 1.0.degree. C.
below its gelling temperature, (d) withdrawing the dipping pins
from the aqueous composition obtaining a film on the dipping pins
and (e) drying the film on the dipping pins at a temperature above
the gelling temperature of the aqueous composition so as to obtain
molded capsule shells on the pins.
[0034] Steps (a) and (b) can be performed in any order. By
contrast, steps (c) to (e) are to be performed in the order they
are presented and after steps (a) and (b).
[0035] In step (a) the aqueous compositions of the invention can be
used. An optional adjustment of the HPMC concentration can be
performed to meet the viscosity ranges indicated above.
[0036] In step (b), the temperature range of pre-heated pins is
55-95.degree. C. meaning that this is the pin temperature when pins
are dipped. Preferably the temperature is 60-90.degree., more
preferably 60-85.degree. C., more preferably 65-85.degree. C., even
more preferably 70-80.degree. C. It is preferred that such
temperature be chosen according to the desired capsule size. By
"according to the capsule size" it is meant that the smaller the
pin dimension, the higher the temperature. For example, for an HPMC
type 2906 (USP classification) and within the HPMC weight ranges
defined above for the aqueous composition, for a capsule size 00
(conventionally considered a large capsule size), the pin
temperature is preferably between 70 and 80, for a capsule size 1
(conventionally considered a medium capsule size), the pin
temperature is preferably between 80 and 90, and for a capsule size
4 (conventionally considered a small capsule size), the pin
temperature is preferably between 85 and 95.
[0037] In step (c), the dipping composition is maintained at a
temperature of 10.degree. C. to 1.0.degree. C., preferably
6.degree. C. to 2.0.degree. C., below its gelling temperature. For
example, if a dipping composition has a gelling temperature of
about 36.0.degree. C., it can be maintained at a temperature of for
example about 34.0.degree. C.
[0038] After being withdrawn from the dipping composition, the pins
can be turned from a "top-down" dipping position to a "top-up"
drying position according to conventional capsule molding
processes. In this step the pins are rotated about a horizontal
axis of about 180.degree. with respect to the dipping position of
step (c).
[0039] By drying in step (e) the object is to reduce the water
content in the capsule shells on the pins. Generally, the water
content in the molded capsule shells is reduced from around 80% to
around 7% by weight, based on the total weight of the molded
capsule shells. An indicative water content in the capsule shell of
the invention is provided below.
[0040] Step (e) can be performed according to any technique
commonly known for this purpose, for example by placing the pins in
conventional ovens, for a sufficient period of time, typically from
30 to 60 minutes.
[0041] In a preferred embodiment, step (e) is performed as
disclosed in the co-pending patent application, filed by the
instant Applicant on Oct. 26, 2006, having the title "Capsule
formation" and having filing number U.S. 60/863,040. According to
such a preferred embodiment, it has been found that subjecting the
film to a particular combination of temperature and relative
humidity provides excellent results.
[0042] Thus, preferably step (e) comprises a step (e1) where the
dipping pins with the molded capsule shells are subjected to a
temperature of 50 to 90.degree. C. at a RH of 20 to 90%,
preferably, T is 55 to 85.degree. C. at a RH of 20 to 70%, more
preferably T is 60 to 85.degree. C. at a RH of 20 to 60%.
[0043] Generally the duration of step (e1) is 90-480 seconds,
preferably 120-300 seconds, more preferably 120-240 seconds.
[0044] Step (e1) is preferably followed by a step (e2), where the
pins are subjected to a temperature of 30 to 60.degree. C. at a RH
of 20 to 90%, preferably, T is 35 to 55.degree. C. at a RH of 20 to
70%, more preferably T is 35 to 50.degree. C. at a RH of 20 to
60%.
[0045] Generally the duration of step (e2) is 30 to 60 minutes.
[0046] Both steps (e1) and (e2) can be performed in an oven. The
ovens used are preferably tunnels which allow a continuous
processing.
[0047] The term "relative humidity" is used herein to mean the
ratio of the actual water vapor pressure at a given temperature to
the vapor pressure that would occur if the air were saturated at
the same temperature. There are many technologies for humidity
measurement instruments known to the skilled person, all of which
would give substantially the same RH measure.
[0048] In the current description, if not otherwise indicated, by
"capsule" it is meant a hard capsule consisting of two co-axial,
telescopically-joined parts, referred to as body and cap. Normally,
caps and bodies have a side wall, an open end and a closed end. The
length of the side wall of each of said parts is generally greater
than the capsule diameter. Thus, the HPMC hard capsules of the
present invention do not structurally depart from the conventional
definition of hard capsules. "Capsule" refers to both empty and
filled capsules.
[0049] The molded capsule shells mentioned to above, generally
refer to both bodies and caps, depending on the shape of the mold
pin. Thus, after step (e) the dried capsule shells on the dipping
pins can be processed according to conventional steps. This means
that in general after step (e), the capsule shells (bodies and
caps) are stripped from the pins. This step can be followed by
cutting the stripped shells to a desired length.
[0050] Typically, hard capsule dip-molding manufacturing processes
encompass an additional step of lubricating the pins so as to make
it easier to strip the capsule shells from the pins. Lubrication is
normally achieved via the application of a demolding agent to the
pins surface.
[0051] In the instant invention any demolding agent and lubricating
apparatus conventionally used for HPMC capsules can be used.
[0052] After stripping and cutting, the bodies and caps may be
fitted together for obtaining a complete capsule. Preferably, the
capsule cap and body are telescopically joined together so as to
make their side walls partially overlap and obtain a capsule.
[0053] "Partially overlap" also encompasses an embodiment wherein
the side walls of caps and bodies have substantially the same
length so that, when a cap and a body are telescopically joined,
the side wall of said cap encases the entire side wall of said
body. This embodiment is particularly advantageous for the
manufacture of tamper-proof capsules to be used for example in the
context of double-blind trials.
[0054] In one embodiment, the dipping pins are designed so as to
create pre-locking means in caps and bodies formed thereon.
Suitable pins design and pre-locking means are disclosed for
example in EP 110500 B1, notably lines 27-31 of column 2 and for
example FIG. 34. If caps and bodies are provided with pre-locking
means, the bodies and caps obtained after stripping, are first
jointed to obtain a pre-locked capsule. This pre-locked capsule can
then be re-opened, filled and locked to its final position.
[0055] Once filled, the capsules can be made tamper-proof by using
any solution conventionally used in the field of hard capsules to
make the joint permanent. Banding so or sealing are suitable
techniques. Sealing is a technique well known in the field of hard
shell capsules. Various alternative techniques are currently used
for this purpose. A suitable procedure is disclosed for example in
U.S. Pat. No. 4,539,060 and U.S. Pat. No. 4,656,066. Many
improvements of sealing procedure are currently available.
[0056] According to a know sealing process, the capsule is (i)
contacted with a sealing fluid, (ii) excess sealing fluid is
removed from the surface and (iii) the capsule is dried so as to
induce curing and make the seal permanent.
[0057] For the HPMC capsules obtained with the invention,
alcohol/water mixtures can be used as sealing fluids, such as
ethanol/water mixtures.
[0058] The good sealing quality obtained makes the sealed capsule
of the instant invention particularly suitable for the manufacture
of leakage-free dosage forms particularly for use in the
administration of substances in liquid form. By "sealing quality"
it is meant either the visual quality and/or the adhesion strength
of the sealing.
[0059] The above aqueous compositions and process are particularly
suitable for manufacturing HPMC hard capsules that dissolve at a
rate comparable to conventional gelatine capsules. Such capsules
can be manufactured at an industrial scale with process speeds
comparable to gelatine capsules. Their mechanical properties are
better than those of conventional gelatine capsules since they are
less brittle, particularly under extremely dry atmosphere. Their
visual appearance is similar to that of gelatine capsules.
[0060] In a third aspect, the present invention relates to a HPMC
hard capsule shell containing a HPMC having a methoxy content of
27.0-30.0% (w/w), a hydroxypropoxy content of 4.0-7.5% (w/w) and a
viscosity of 3.5-6.0 cPs as a 2% weight solution in water at
20.degree. C., wherein the methoxy and hydroxypropoxy contents are
expressed according to the USP30-NF25 and wherein the viscosity is
measured according to the USP method for cellulose derivatives.
[0061] In a preferred embodiment, the capsule shells are obtainable
by the aqueous composition and/or process disclosed above.
[0062] In a preferred embodiment, the capsule shell contains the
HPMC in an amount between 70 and 99%, preferably between 80 and 99%
by weight based on the shell weight. If no other film-forming
polymers are present, the HPMC is preferably between 92% and 99%,
more preferably between 93 and 98%, even more preferably between
94% and 97% by weight based on the shell weight.
[0063] In a preferred embodiment, the capsule shell contains
between 0% and 25%, preferably between 0% and 10% by weight based
on the shell weight of additional non animal-derived film-forming
polymers as defined above.
[0064] In a preferred embodiment, the capsule shell contains water
between 1 to 8%, preferably between 7 and 2%, more preferably
between 6 and 3% by weight based on the shell weight.
[0065] In a preferred embodiment, the capsule shell contains one or
more pigments as those discussed above, between 0 and 10%,
preferably between 0.001 and 5%, more preferably between 0.01 and
3%, by weight based on the shell weight.
[0066] In a preferred embodiment, the capsule shell contains one or
more dyes between 0 and 5%, preferably between 0.001 and 3%, more
preferably between 0.01 and 2%, by weight based on the shell
weight.
[0067] In a preferred embodiment, the capsule shell contains one or
more plasticizers as those discussed above, between 0 and 10%,
preferably between 0.001 and 5%, more preferably between 0.01 and
3%, by weight based on the shell weight.
[0068] In a preferred embodiment, the capsule shell contains one or
more antibacterial agents between 0 and 2 preferably between 0.001
and 1%, more preferably between 0.01 and 0.5%, by weight based on
the shell weight.
[0069] In a preferred embodiment, the capsule shell contains one or
more flavourings agents between 0 and 2%, preferably between 0.001
and 1%, more preferably between 0.01 and 0.5%, by weight based on
the shell weight.
[0070] In a preferred embodiment, the HPMC hard capsule shell
presently disclosed can be used for the manufacture of tamper-proof
pharmaceutical dosage forms. To this end, it is particularly
advantageous if the capsule shell is as disclosed in EP 110500 B1.
In this preferred embodiment, the HPMC hard capsule shell comprises
coaxial cap and body each of the cap and body having a generally
cylindrical side wall, an open end and a closed end region, the
side wall of each of said parts is substantially greater than the
capsule shell diameter, the cap and body being adapted to be joined
in telescopic relationship wherein, when the cap and body are fully
joined in telescopic relationship, the only portion of the body
which is exposed is the closed end region, and wherein the closed
end region has an outer surface which is of such a configuration as
to resist being gripped, whereby separation of the cap and body is
impeded, and wherein when the cap and body are fully joined in
telescopic relationship, the inner side wall of the cap is
substantially totally overlapped by the outer side wall of the
body. In other words, when the cap and body are fully joined in
telescopic relationship, the side wall of the cap encases the
entire side wall of the body. Thus, in use, only the body closed
end is exposed and presents a minimal surface for gripping and
withdrawal of the body from within the cap, thereby impeding
separation of the capsule shell.
[0071] The closed end region of either the body and the cap may,
for example, have a configuration which is generally
hemispheroidal, pyramidal, conical or flat.
[0072] For additional security, it is preferred that the body and
the cap further include mutual locking means comprising one or more
circumferentially extending ridges and/or grooves. Thus, the
capsule shell may be such that the side wall of one of the cap and
body has a locking means comprising one or more circumferentially
extending ridge extending either (i) radially inwardly from an
inner surface of the side wall of the cap or (ii) radially
outwardly from an outer surface of the side wall of the body, as
the case may be.
[0073] Alternatively, or in addition, the side wall of the other of
the cap and body has one or more circumferentially extending groove
extending either (i) radially inwardly from the outer surface of
the body or (ii) radially outwardly from the inner surface of the
cap, as the case may be, and engaging a respective ridge.
[0074] It is preferred that the capsule shell further includes
venting means to permit air to escape from within the capsule when
joined, wherein the or each circumferentially extending ridge
comprises two or more segments so that spaces between the segments
act as vents to permit air to escape from within the capsule when
the cap and body are being joined.
[0075] It is preferred that the side wall of one of the cap and
body has a pair of diametrically opposed integral indents extending
either (i) radially inwardly from the inner surface of the side
wall of the cap or (ii) radially outwardly from the outer surface
of the side wall of the body, as the case may be; and the diametric
spacing of the indents is, in the case (i), less than the outside
diameter of the open end of the body or, in the case (ii), greater
than the inside diameter of the open end of the cap, such that the
body can enter the cap and permit air to escape from within the
capsule when the cap and body are being joined.
[0076] For storage and/or transportation purposes, it is preferred
that the capsule shell may also include means for pre-locking the
partially joined caps and bodies in a constant predetermined
relative position prior to filling and final joining. This
embodiment is particularly advantageous when it is desired to
include step [I-1] in the process of the invention.
[0077] Preferably, bodies have a reduced diameter in the area of
their open end in order to avoid abutment when they are
telescopically housed within caps.
[0078] Alternatively, or in addition, caps have a reduced diameter
in the area of their open end, thereby resulting in improved
engagement between them and the region of the side wall of the
bodies adjacent the closed end region of the bodies, as further
resistance to tampering.
[0079] In a fourth aspect the present invention relates to a HPMC
hard capsule comprising a capsule shell as defined above and one or
more substances filled therein.
[0080] All kinds of suitable compounds may be filled in the capsule
of the present invention including pharmaceuticals, vitamins or
nutrients, plant powder extracts etc, including particularly
hygroscopic ingredients.
[0081] When used as dosage form for drugs, capsules of the
invention typically comprise for example from 0.001 g to 2.0 g of
active ingredient, optionally mixed with one or more
pharmaceutically acceptable excipients.
[0082] In one embodiment, the HPMC hard capsule presently
disclosed, optionally sealed, can be used in the context of dry
powder inhalers (also commonly know by the acronym DPIs). In this
embodiment, the superiority of the presently disclosed capsules
over conventional HPMC capsules can be traced back for example to:
[0083] capsules improved colour/transparency, [0084] reduced
stickiness of the internal surface of caps and bodies side walls
due for example to a reduced amount of demolding agent required in
capsule manufacturing process, [0085] improved quality of capsule
sealing.
[0086] All of the capsule embodiments disclosed above can be
produced on conventional capsule-making machines utilizing
dip-moulding technology. The skilled person can find additional
background information on dip-moulding process for gelatine
capsules in U.S. Pat. No. 4,893,721.
[0087] In a fifth aspect, the present invention relates to
hydroxypropyl methyl cellulose hard capsule shells and capsules as
defined above, for use in the administration to a subject of
substances, particularly pharmaceutical substances, in liquid or
solid form.
[0088] In a sixth aspect, the present invention relates to the use
of hydroxypropyl methyl cellulose hard capsule shells and capsules
as defined above for the manufacture of pharmaceutical dosage forms
suitable for the administration to a subject of pharmaceutical
substances in liquid or solid form.
[0089] By "solid form" it is preferably meant powder form, and the
administration of the substance(s) may preferably entail the use of
a dry powder inhaler.
[0090] By "subject" it is preferably meant a human or animal
subject, more preferably a human subject.
[0091] Preferred conditions for implementing the compositions
described above also apply to the other subjects of the invention
envisaged above such as processes and capsules.
[0092] The scope of the invention can be understood better by
referring to the examples given below, the aim of which is to
explain the advantages of the invention. Unless otherwise
specified, all parts and percentages are by weight. Composition
viscosities were determined by Brookfield viscometer.
EXAMPLE 1
Aqueous Composition for the Manufacture of Hydroxypropyl Methyl
Cellulose Hard Capsules
[0093] A 5 kg composition of 18.8% HPMC type 2906 (methoxy content
28.7%, hydroxypropoxy content 5.4%) of 4.4 cPs viscosity at 2%
concentration (w/w) was prepared as follows:
[0094] The HPMC powder is dispersed into hot water at 75.degree. C.
under stirring. Formation of foam is observed. After complete
dispersion of the powder, the temperature is kept at 75.degree. C.
under very gentle stirring for de-foaming of the dispersion. Then
the dispersion is cooled down to 10.degree. C. under gentle
stirring for obtaining dissolution of the HPMC. After keeping the
composition for more than 30 minutes at 10.degree. C., a dipping
composition ready for use in capsule manufacturing is obtained.
[0095] The HPMC composition gelling temperature was determined by
viscosity measurement by progressively heating the composition. The
gelling temperature found was 34.degree. C.
EXAMPLE 2
Manufacture of Hard Capsules
[0096] The composition prepared in example 1 is poured into the
dipping dish of a pilot equipment of hard capsule manufacturing.
The dip pins of size 0 are pre-heated at 75.degree. C., while the
dipping composition is maintained at 32.degree. C. At this
temperature, the viscosity of the dipping composition was 2000 cPs.
Capsules of size 0 are manufactured by the conventional dipping
process, but with the pre-heated pins. After the dipping, the
capsules are dried in an oven with hot air at 60.degree. C. and 40%
RH for 3 minutes then with hot air at 40.degree. C. and 40% RH.
[0097] The capsules obtained are of high quality: good and
standardized dimension (the top wall thickness is >140 .mu.m),
high transparency (similar to hard gelatin capsules), excellent
dissolution and mechanical performance.
EXAMPLE 3
Optimal Pre-Heating Temperature for Pins
[0098] Example 2 was re-run but with dip pins pre-heated at
60.degree. C. instead of 75.degree. C. It is noted that pin size 0
is considered a medium-large dimension.
[0099] The gelling on the pins after dipping was not optimal to
obtain commercially acceptable capsules. Solution partially flew
down the pin during drying, leading to the top wall thickness less
than 50 .mu.m.
[0100] Conclusion: 60.degree. C. as pin pre-heating temperature is
less preferable than 75.degree. C. for size 0 capsule
manufacturing.
EXAMPLE 4
Mechanical Properties Under Stress Conditions of the Capsules of
Example 2
[0101] The mechanical properties of the capsules of example 2 were
tested under stress conditions as follows:
[0102] A stainless steel cylinder weighing 100 g was allowed to
fall from a height of 8 cm onto empty capsules one by one. The
percentage of broken capsules is reported hereunder.
[0103] Results:
TABLE-US-00001 % of broken capsules Storage conditions RH %
Capsules of example 2 Gelatine capsules 2.5 0 24 10 0 13 23 0 2 33
0 0 50 0 0 RH = Relative Humidity
[0104] Conclusions: capsules of example 2 do not exhibit any
brittleness even at extremely low relative humidity.
EXAMPLE 5
In Vitro Dissolution Performance of the Capsules of Example 2
[0105] The capsules of example 2 were tested according to the USP
monograph method for dissolution of acetaminophen capsules.
[0106] Results:
TABLE-US-00002 Dissolution medium Time % Acetaminophen dissolved pH
1.2 15 min 32 30 min 68 45 min 88 60 min 95 75 min 100
Demineralised water 15 min 36 30 min 70 45 min 88 60 min 95 75 min
98 pH 6.8 potassium 15 min 29 phosphate 30 min 67 45 min 87 60 min
96 75 min 99
EXAMPLE 6
Determination of the Gelling Temperature
[0107] A 18.8% w/w solution in water of HPMC type 2906 is prepared
as described in example 1. The viscosity is monitored with a
Brookfield Model DV-II viscometer at different temperatures by
increasing the measure cell temperature by steps (with 10 minutes
equilibrium at each step). The results are reported in the graph
below. It can immediately be appreciated that the gelling
temperature is around 34.degree. C.
COMPARATIVE EXAMPLE 1
Manufacture of Capsules with HPMC Type 2910
[0108] A 5 kg composition of 26.3% HPMC type 2910 of 3 cPs
viscosity at 2% was prepared as in examples 1 and 2. The gelling
temperature found was 47.degree. C. While the dipping composition
is maintained at 45.degree. C. Capsules of size 0 were manufactured
under the same process conditions as in the above example 2
(viscosity of the dipping composition 2000 cPs at 45.degree.
C.).
[0109] Results: an acceptable dimension is obtained (the top wall
thickness is above 140 .mu.m). However, too brittle capsules are
obtained since almost all the capsules break during their stripping
from the dipping pins.
COMPARATIVE EXAMPLE 2
Manufacture of Capsules with HPMC Type 2910
[0110] A 5 kg composition of 17.9% HPMC type 2910 of 6 cPs
viscosity at 2% was prepared as in examples 1 and 2. The gelling
temperature found was 50.degree. C. While the dipping composition
is maintained at 48.degree. C. Capsules of size 0 were manufactured
under the same process conditions as in the above example 2
(viscosity of the dipping composition 2000 cPs at 48.degree.
C.).
[0111] Results: an unacceptable dimension is obtained (insufficient
gelling behaviour, composition on the pins partly flowing down, top
wall thickness less than 80 .mu.m). Therefore, the advantage in
using an HPMC type 2906 against using other HPMCs such as HPMC type
2910 can be seen.
COMPARATIVE EXAMPLE 3
Manufacture of Capsules with Too Low Dipping Solution Viscosity
[0112] Example 2 was re-run but with a dipping solution of a
viscosity at 900 cPs measured at 32.degree. C. This decrease in
viscosity was obtained by adding water to the composition.
[0113] The gelling on the pins after dipping was not sufficient,
solution flowing down occurred during the drying, leading to the
top wall thickness less than 50 .mu.m, much to low for being
acceptable. Results: a viscosity of 900 cPs for the dipping
solution is too low to have an acceptable gelling ability and top
wall thickness.
* * * * *