Note: Descriptions are shown in the official language in which they were submitted.
PD-7038-64-SIL
WARNER-LAMBERT COMPANY
MORRIS PLAINS, USA
New composition comprising a hydrophilic pol~mer
and a hydrophilic material different therefr~m
The present invention relates to compositions comprising a
dispersion medium consisting of a melt comprising a hydrophilic
polymer, and a disperse phase comprising at least one
hydrophilic, preferably hygroscopic, material different
therefrom, said compositions having improved dissolution
characteristics. The terms hydrophilic polymer, dispersion
medium, disperse phase, hydrophilic material and hygroscopic
material are defined hereinafter.
It is known that many hydrophilic polymers, which in the dry
state (i.e. in the ahsence of water) cannot be melted and
decompose at an elevated temperature, form a thermoplastic melt
in the presence of a defined amount of water. An example of
such a hydrophilic polymer is gelatin. It is also known that
hydrophilic polymers that do melt in the dry state at elevatecl
temperature form thermoplastic melts at those temperatures also
in the presence of defined amounts of water.
Such hydrophilic polymers can be treated at an elevated
temperature to form a melt. The process is conveniently carried
out in an injection moulding machine or extruder. The hydrophilic
polymer is fed through the hopper onto a rotating, reciprocating
screw. The feed material moves along the screw towards the tip.
During this process, its temperature is increased by means of
external heaters around the outside of the barrel and by the
shearing action of the screw. Starting in the feed zone and
continuing in the compression zone, the particulate feed becomes
gradually molten. It is then conveyed ~hrough the metering zone,
where homogenization of the melt occurs, to the end of the screw.
The molten material at the tip can then be further treated by
2 PD-7038-64-SIL
injection moulding or extrusion or any other known technique to
treat thermoplastic melts, to obtain shaped articles.
This treatment is descrlbed in the European Patent Application
No. 83 301 643.9 (Publication No. 0 090 600) which is
incorporated herein by reference.
The preferred hydrophilic polymers of the present invention are
natural hydrophilic polymers and especially gelatin. Such gelatin
is made preferably from acid or alkaline processed ossein, acid
processed pigskin, or alkaline processed cattle hide. Said types
of various gelatin have a molar mass range of 10,000 to 2,000,000
grammes per mole (g/mol) or a molar mass range of 10,000 to
2,000,000 and 10,000,000 to 20,000,000 g/mol. Such gelatins are
known.
However, other hydrophilic polymers as described herein are
included in this invention. Hydrophilic polymers are polymers
with molar masses from approximately 103 to 107 g/mol carrying
functional groups in their backbone and/or in their side-chains
which are capable of participating in hydrogen bonding. Such
hydrophilic polymers exhibit in their ~ater absorption isotherm
in the temperature range between approximately 0 to 200 C an
in~lection point close to the water activity point at 0.5.
Articles made from such hydrophilic polymer melts are useful for
many applications. An important property is the capability of
such articles to take up water and to disintegrate.
For many purposes the speed of disintegration must be high,
which, for example, is the case for pharmaceutical containers.
Pharmaceutical containers in the form of conventional hard
gelatin capsules made by the known dip moulding process generally
have a dissolution time which is somewhat shorter than that for
similar containers but made by an injection moulding process.
It is, therefore, an object of the present invention to reduce
the dissolution ~ime of such injection moulded capsules.
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3 PD-7038-64-SIL
According to the present invention there is provided a
composition of ma-tter capable of being formed into articles
having substantial dimensional stability and improved dissolution
characteristics, comprising a medium and a phase, the medium
functioning as a dispersion medium with respect to the phase, the
phase likew.ise functioning as a disperse phase with respect to
the medium, the phase being present in the composition at a
concentration sufficient to effect an increase in dissolution of
articles in comparison with the rate of dissolution of articles
made from a composition absent said phase, the medium consisting
of a solidified hydrophilic polymer and the phase comprising at
least one hydrophilic material which is substantially insoluble
in the medium forming the hydrophilic polymer.
This composition may be in the form of a powdery mixture of its
components or in the form of a melt or in a solidified form as
obtainable from such a melt, for e~ample, in the form of solid
particles such as granulates, pellets or powders. These forms of
the novel compositions are primarily useful themselves fo~ making
finished articles according to the present invention. Said
powdery mixtures or said solidified forms may be processed into
a melt from which finished articles may be formed.
The invention particularly provides shaped articles as obtained
from the composition, which articles are selected from the group
consisting of bottles, sheets, films, packaying materials, pipes,
rods, laminated films, sacks, bags, foams, granules, powders, and
pharmaceutical containers.
The invention further provides shaped articles as above when used
as a carrier material comprising a member selected from
pharmaceutically and veterinarilly active compounds.
The invention s~ill further provides a proaess for produ~ing a
composition of matter capable of being formed into articles
having substantial dimensional stability and improved dissolution
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4 PD-7038-64-SIL
characteristics, which composition comprises a medium and a
phase, the medium functioning as a dispersion medium with respect
to the phase, the phase likewise functioning as a disperse phase
with respect to the medium, the phase being present in the
composition at a concen-tration sufficient to effect an increase
in dissolution of articles in comparison with the rate of
dissolution of articles made from a composition absent the phase,
the medium consisting of a solidified hydrophilic polymer and the
phase comprising at least one hydrophilic material which i5
substantially insoluble in the medium forming hydrophilic
polymer, which process comprises heating said hydrophilic polymer
to a temperature above the melting point and glass transition
temperature of the hydrophilic polymer for a time sufficient to
effect melt formation, characterised in that the material which
functions as the disperse phase is added to the hydrophilic
polymer either before, during or after melt formation.
The invention still further provides a process of shaping the
composition to form shaped articles, which process is selected
from injection moulding, blow moulding, extrusion, co-extrusion,
compression moulding, vacuum forming, foaming and thermoforming.
The disperse phase is preferably comprised by a fibrous polymer
selected from polysaccharides, preferably from the group
consisting of cellulose, chitin, starch, or chitosan which
preferably are cross linked and wherein some of the hydroxyl
groups of the constituent anhydro-glucose units are substituted.
Alternatively, the disperse phase may be a polyvinylp~rrolidone
polymer.
Such fibrous polymers have been added to gelatin in the dip
moulding process for the production of hard gelatin capsules in
a concentration of up to 10~. ~owever, no increase in the
dissolution rate of capsules so produced was noticed, when
compared to like capsules but madP in the absence of said fibrous
polymers.
PD-7038-64-SIL
It was therefore surprising to find that, a:Lthough the mixture
according to the present invention undergoes melt formation in
the presence of water at elevated temperatures and pressures,
when present at lcw concentrations such fibrous polymers enhance
the dissolution characteristlcs of the solidified melt.
The invention will be further apparent from the following
description with reference to the accompanying examples.
The terms "dispersion medium" and "disperse phase" within the
context of the invention are to be construed in accord with the
following: The composition of the present invention consists of
material comprised by a medium and material comprised by a phase.
It is a requirement of the present invention that the medium be
incompletely miscible with the phase when both are present in the
composition, i.e., that the phase is dispersed in, but not
dissolved in, the material comprising the dispersion medium. The
phase may thus include course particles or particles of smaller
size to form colloidal systems, or larger particles wh~n such
behave likewise when present in the thermoplastic melt.
The term "hydrophilic material" within the context of the
invention means a material which is water-soluble and water
swellable, i.e. a material which is able to take up water at room
temperature in an amount of at least 10 grams per 100 grams of
material, and preferably in an amount o~ at least 20 grams per
100 grams of material.
The term "hygroscopic material" within the context of the
invention is to be construed in accord with the following: A
hygroscopic material is one which readily absorbs and/or absorbs
and retains moisture from the environment at room temperature,
but does not liquify due to dissolution of said material by
absorption, adsorption and retention of the moisture. Such
material may adsorp and/or absorb and retain water at a rate of
up to 1000 times its own weight.
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6 PD-703~-6D,-SIL
The term "hydrophilic polymer" as def ined above includes the
following, insofar as they do no-t form a disperse phase, within
the context of this invention: substantially water-soluble
polymers, for example animal gelatin, vegetable gelatins,
proteins such as sunflower protein, soybean proteins, cotton seecl
proteins, peanut proteins, rape seed proteins, acrylated
proteins; substantially water-soluble polysaccharides,
alkylstarches, hydroxyalkyl starches and hydroxyalkylalkyl
starches, such as: methylstarch, hydroxymethylstarch,
hydroxyethyl starch, hydroxypropyl starch, hydroxyethylmethyl
starch, hydroxypropylmet~yl starch, hydroxybutylmethyl starch,
starch esters and hydroxyalkyl starch esters such as: starch
acetatephthalate, Hydroxypropylmethyl-starch phthalate;
carboxyalkylstarches, carboxyalkylalkylstarches; alkylcelluloses,
hydroxyalkyl celluloses and hydroxyalkylalkyl celluloses, such
as: methylcellulose, hydroxymethylcellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose,
hydroxypropylmethyl cellulose, hydroxybutylmethyl cellulose,
cellulose esters and hydroxyalkyl cellulose esters such as:
cffllulose acetatephthalate (CAP), Hydroxypropylmethyl cellulose
phthalate (HPMCP); carboxyalkylcelluloses,
carboxyalkylalkylcelluloses; esters such as
carboxymethylcellulose and their alkali metal salts,
water-soluble synthetic polymers such as: polyacrylic acids and
polyacrylic acid esters, polymethacrylic acids and
polymethacrylic acid esters, polyvinyl alcohols, poly~rinyl
acetatephthalates (PVAP~, polycrotonic acids; polyitaconic acid,
polymaleic acid; suitable are also phthalated gelatin,
crosslinked gelatin, shellac, gelatin succinate, cationically
modified acrylates and methacrylates possessing, for example, a
tertiary or quaternary amino group, such as the diethylaminoethyl
group, which may be quaternized if desired; and other similar
polymers insofar they are essentially water-soluble.
The term "hydrophilic polymer" within the context of this
invention means a polymer which is essentially water-soluble,
i.e. it is able to take up water at a rate of at least 50 grams
7 PD-7038-64-SIL
of water per 100 grams of the polymer at room temperature.
If the hydrophilic polymer is not gelatin and only admixed to the
gelatin, it is sufficient that said hydrophilic polymer is only
"water-swellable", i.e. it takes up at least 10 grams of water
per lO0 grams of the polymer at room temperature. Such an
admixed hydrophilic polymer, must, howe~er, not form a separate
phase from the gelatin. Of course, it is possible to use also
a mixture of these polymers.
Preferred is gelatin as defined above and gelatin as occurs i.n
its partial salt form, an~ as is used in the dip moulding of hard
gelatin capsules. If other hydrophilic polymers are mixed with
gelatin these may be mixed in any desired ratio. Preferably
gelatin is present in an amount of at least 50 %, preferably in
an amount of at least 7~ % and most preferably in an amount of
at least 90 % by weight of the total composition.
If other essentially water-soluble polymers are admixed to the
gelatin, then synthetic polymers are preferred such as
polyacrylic acids, polyacrylic acid esters, polymethacrylic
acids, polymethacrylic acid esters, polyvinyl alcohols.
Such other hydrophilic polymers as mentioned may optionally be
added in any desired amount preferably in an amount up to 50 %,
preferably up to 30 % and most preferably within a ratio of
gelatin: other hydrophilic polymer of 90 - 97 : 10 - 3 % by
weight calculated to the dry components of the composition.
The water content of such a hydrophilic polymer/water composition
is about 1 - 40% water by weight of the total composition and
preferably about 5 - 25 %. However, in order to work with the
material near its equilibrium water content to which it gets when
it is finally exposed to the free atmosphere, a water content of
8 - 20 %, preferably of 10 - 16 % ~y weight calculated to the
total composition should preferably be used in processing. If,
for example, the gelatin contains only 1 % to 8 % of water it may
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8 PD-7038-6~-SIL
be advisable to add some plasticizer in order to ease processing.
This should be done in an analogous manner for the other
hydrophilic polymers.
For such hydrophilic polymers which are not gelatin the water
content may be lower than the water content generally indicated
above as is the case for several of the cellulose derivatives.
However, this is merely an experimental optimization which can
easily be carried out by one skilled in the art.
The hydrophilic material of the disperse phase has a meltlng
point which preferably is higher than the glass transition
temperature of the hydrophilic polymer and preferably absorbs up
to a thousand times its own weight in water. The precise amounts
of water absorbed by the material vary according to its nature
and the ionic strength of the aqueous environment in which it is
situated. For example, the amount of water absorhed is generally
reduced as ionic strength is increased.
The material comprises a pol-ymer of glucose moieties, and
preferably is selected from the group consisting o~ cellulose,
chitin, starch and chitosan.
Preferably, at least some of the hydroxyl groups of
anhydroglucose moieties comprised by the polymer are substituted,
with, for example, a member from the group consisting of carboxy-
carboxyalkyl, sulfoalkyl, and salts thereof, and
dialklyaminoalkyl, - or quaternary derivative thereof. Such
derivatives are, for example, carboxymethylcellulose,
diethylaminoethyl cellulose, triethanolamine cellulose,
polyethyleneimine cellulose, and carboxymethyl starch.
In the preferred embodiment, the disperse phase is comprised by
the compounds mentioned above, which are internally cross linked.
These polymers are preferably substituted to a degree of between
0.5 and 1.2 and preferably are substituted to a degree of about
0.7. Preferably such materials are of a strand or fibrous type,
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9 PD-7038-64-SIL
and have an average strand or average fibre length of from about
10 to about 500um. More preferred such average strand or fibre
sizes are from about 20 to about 300um, and most preferred such
sizes are from about 20 to about lOOum. Said materials are
preferably cross linked to such an extent that they are
substantially water-insoluble. Preferred cross linked materials
include cross-linked carboxymethyl starch, internally cross-
linked carboxymethyl cellulose and salts thereof, and cross-
linked cellulose amines possessing tertiary or quaternary amino
groups.
Internally cross linked sodium carboxymethyl cellulose is listed
in the US-National Formulary as Croscarmellose Sodium Type A as
sold by FMC Corporation (Philidelphia, USA) under the Trade name
Ac-Di-Sol. The average strand or fibre size of said cross-linked
carboxymethyl cellulose is from about 70 to about 80um, and it
has been used previously at concentrations of between 2 and 6%
as a disintegrant in tablets and capsules made by a dry cold
compression process. A molten system comprising a water-
containin~ hydrophilic polymer melt, where generally temperatures
of between 90 and 180C as well as high pressures are used is
considerably different from a conventional pharmaceutical tablet
manufactured at room temperature using substantially dry
materials.
Chemically modified suitable starches comprised by the material,
such as carboxymethyl starch or sodium starch glycolate are
available under the Trade names of Explotab ~Edward Mendell
Company Incorporated Carmel, New York) and Primojel (Generichem
Corp. Little Falls, New Jersey). The average fibre or strand
size of said modified starches is about 70um.
A further material suitable as the hydrophilic material of the
disperse phase is microcrystalline cellulose as sold under the
trade name Avicel PH-101 by Fluka Chemie AG of Industries~arsse
25, CH-9470 Buchs, Switzerland. The avera~e fibre or strand size
of said microcrystalline cellulose is from about 20 to about
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PD-7038-64-SIL
lOOum, depending upon the grade used.
A still further material suitable as the hydrophilic material of
the disperse phase is a cross linked polyvinylpyrrolidone as sold
under the Trade name Polyplasdone XL (G~F Corp., New York), or
Kollidon. The average fibre or strand size of said
polyvinylpyrrolidone depends on the precise grade used, but is
typically in the range of from about 20 to about 250um.
Pullulan, or pullulan derivatives, which are, or are rendered
substantially insoluble in the hydrophilic polymer, by cross
linking or acetylation, for example, may be used as the
hydrophilic material of the disperse phase.
The pullulan or derivative may be substituted to between about
0.5 and 1Ø
The hydrophilic material is present in the thermoplastic mèlt at
a concentration of between about 0.1 and 4%, by weight, based on
the weight of the thermoplastic melt. Preferably the material
is present in the thermoplastic melt at a lower concentration
of between about 0.3 and about 2%, by weight, based on the weight
of the thermoplastic melt, and most preferably is present in the
thermoplastic melt at a concentration of between about 0.5 and
about 1.5%, by weight, based on the weight of the thermoplastic
melt.
The hydrophilic polymer may be mixed with the material of the
disperse phase, and optionally other additives as mentioned
herein, in any desired sequence. For example the hydrophilic
polymer may be mixed with all the additives including the
material and then heated for des~ructurization to form a melt.
The granular size of the starting material is not critical and
it can be processed in standard e~uipment which is commercially
a~ailable.
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1 1 PD-7038-64-SIL
The hydrophilic polymer may also be mixed with optional
additives, destructurized and granulated first and then mixed
with the hydrophilic material of the disperse phase fox further
processing.
The hydrophilic polymer is preferably mixed with the additives
as named herein together with the material to yield a fxee
flowing powder useful for contimlous processing and
destructurized and either granulated or directly moulded into a
shaped article, e.g. a pharmaceutical container.
Thus, the hydrophilic polymer and all the additives can be mixed
in a conventional mixer, the water content of the hydrophilic
polymer being within the range as mentioned above. This mixture
can then be passed through an extruder to produce granulates or
pellets as one form of shaped articles useful for further
processing. However, it is possible to avoid granulating and to
process tha obtained melt directly using down-stream equipment
to ~roduce pharmaceutical capsules, other containers, films,
blown films included,~sheets, profiles, pipes, tubes, foams or
other shaped articles. The sheets can be used for thermoforming.
In order to form a melt of the new polymeric composition
according to this invention, it is suitably heated in a screw and
barrel of an extruder for a time long enough to effect
destructurization and melt formation. Depending on the amount and
types of additives the temperature is preferably within the range
of 50 C to 180 C, preferably within the range of 80 C to 130 C
also of course depending on the type of hydrophilic polymer used.
For this melt formation, the composition is heated preferably in
a closed volume. A closed volume can be a closed vessel or the
volume created by the sealing action of the unmolten feed
material as happens in the screw and barrel of injection moulding
or extrusion equipment. In this sense the screw and barrel of an
injection moulding machine or an extruder is to be understood as
being a closed vessel. Pressures created in a closed vessel
correspond to the vapour pressure of water at the used
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12 PD-7038-64-S~L
temperature but of course pressure may be applied and/or
generated as normal:Ly occurs in a screw and barrel. The preferred
applied and/or generated pressures are in the range of pressures
which occur in extrusion and are known per se, for exa~ple from
up to about 150 x 105 N/m2, preferably up to about 75 x 105 N/m2
and most particularly from about 5 to about 50 x 105 N/m2. The
obtained destructurized hydrophilic: polymer composition is
granulated and ready to be mixed with the further components
according to a chosen mixing and proce.ssing procedure to obtain
the granular mixture of the starting material to be fed to the
screw barrel.
However, the obtained melt in the screw and barrel may be
processed further directly, e.g. injection moulded directly into
a suitable mould, i.e. directly further processed to a final
product if all necessary components are already present.
Within the screw, the granular mixture is heated to a temperature
which is generally within the range of about ~O'C to 180 C,
preferably within the range of about 80 C to 130 C.
The minimum pressures applied under which the melts are formed
correspond to the water vapour pressures produced at said
temperatures. The process is carried out in a closed volume as
explained above, i.e. in the range of the pressures which occur
in extrusion as mentioned above or in the range of pressures used
in injection moulding.
When forming a shaped article by e~trusion the pressures are
preferably as mentioned above. If the melt according to this
invention is injection moulded, for example, the normal ran~e of
injection pressures used in injection mouldin~ is applied, namely
rom about 100 x 105 N/m2 to about 3,000 x lOs N~m2 and preferably
from about 400 x 105 to about 2,200 x 105 N/m2.
The hydrophilic polymer of the pr~sent invention used as startin~
material may ~e mixed with the different known additives e.g.
13 PD-703~-64-SIL
fillers, mould release agents, plasticizers, stabilizers and/or
colouring agents.
Examples of fillers are inorganic fi:Llers, such as the oxides of
magnesium, aluminum, silicon, titanium, etc. calcium carbonate,
preferably in a c~ncentration in the range of abou~ 1 to 50 % by
weight, preferably about ~ to about 10 ~ based on the total
weight of all the components. Other known fillers may be used.
Examples of lubricants are stearates of aluminum, calcium,
magnesium and tin as well as magnesium silicate, silicones, etc.
which ma~ be present in concentrations of about 0.1 to about 5
% preferably at about 0.1 - about 3 % based upon the weight of
the total composition.
Examples of plasticizers include low molecular poly(alkylene
oxides), such as poly(ethylene glycols), poly(propylene glycols),
poly(ethylene-propylene glycols); organic plasticizers of low
molar masses, such as glycerol, pentaerythritol, glycerol
monoacetate, diacetate or triacetate; propylene glycol, sorbitol,
sodiumdiethylsulfosuccinate, triethyl citrate, tributyl citrate,
etc., added in concentrations ranging from about 0.5 to about
25 ~, preferably ranging from about 0.5 to about 10 ~ based on
the total weight of all the components.
Examples of colouring agents include known azo dyes, organic or
inorganic pigments, or colouring agen~s Gf natural origin.
Inorganic pigments are preferred, such as ~he oxides of iron or
titanium, these oxides, known per se~ being added in
concentrations ranging ~rom about 0.001 to about 10 ~, preferably
about 0.5 to about 3 %, based on the weight of all the
components.
The sum of the plasticizer and water contents wi~hin the
hydrophilic component should preferably not e~ceed the values
given for the water content, i.e. about 40 ~, and should most
preferably not exceed about 30 ~, based on the weight of the
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14 PD-7038-64-SIL
composition resp. ~he preferred values for the water content as
given above. It will be obvious to those skilled in the art to
determine the optimum water and plasticiser content for the
different hydrophilic polymeric materials.
The materials may further contain stabilizers, such as
antioxidants and antimicrobial a~ents.
The materials described herein above form thermoplastic melts on
heating and in a closed volume, i.e. under conditions of
controlled water-content and pressure. Such melts can be
processed like conventional thermoplastic materials, using, for
example, injection mouldin~, blow moulding, ex~rusion and
coextrusion (rod, pipe and film extrusion), and compression
moulding, to produce known articles. The articles include
bottles, sheets, films, packaging materials, pipes, rods,
laminated films, sacks, bags, foams, pharmaceutical capsules,
granules or powders. Preferred is the shape of a pharmaceutical
carrier (capsule) made by injection moulding.
Such blended materials may be used also as carrier materials for
active substances, and may be mixed with active ingredients such
as pharmaceuticals and/or agriculturally active compounds such
as insecticides or pesticides for subsequent release applications
of thess ingredients. The resulting extruded materials can be
granulated or worked to fine powders.
The following examples further explain ths invention.
Example 1
100 parts of a commercial gelatin of 240 Bloom adapted to a water
content of 17 % by weight are intensively mi~ed with 2 parts
Ca-Stearate per 100 parts of gelatin and different concentrations
(see below) of thec~isperse phase material Croscarmellose sodium,
in the form of a dry powder so that a freely flowing granulate
is obtained. ~he concentrations of Croscarmellose sodium used
PD-7038-64-SIL
are 1 part per 100 parts of gelatin, 2 parts per 100 parts of
gelatin, and 3 parts per 100 parts of gelatin.
The thus produced granulates are then filled into the hopper of
a screw-injection moulding machine, equipped with an 18 mm screw
(L/D ratio: length over diameter ratio: 25r Arburg Allrounder
220-90-350). The processing condi~ions of this injection moulding
experiment are as follows:
Barrel Temperature profile:
Tb: 90 C / Tm: 125 C / T~: 150 C / T~: 150 C
Screw speed: 160 [rpm]
Injection time: 0.2 seconds
Cycle time: 5 seconds
The injection pressures vary from about 2000 bar for the
gran~late containing no added Croscarmellose to about 2200 bar
for the granulate containing 3 parts Croscarmellose per 100 parts
gelatin.
The various gelatin compositions are moulded into capsule cap and
body parts using a mould with four cavities.
Under these conditions, gelatin capsules of good quality are
obtained under continuous processing - the capsule parts thlls
obtained are not soft and keep their shape unchanged upon
storage.
The capsule containers were filled with identical formulations
of paracetamol powder comprising 85.4 parts paracetamol, 2.~
parts of maize starch, 11.7 parts of microcrystalline cellulose
(Avicel) and 0.26 pats of hydrogenated cottonseed oil. The
containers were filled with the paracetamol formulation using a -
Bosch filling machine.
The dissolution rates of paracetamol from the samples are
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16 PD-7038-64-SIL
determined usiny the standard USP test procedure for paracetamol
capsules. The results of the deterrnination are given in Table
1.
Table 1
% Paracetamol dissolved after
15min 30min 45min
CAPSULE without
disperse phase 61 84 94
CAPSULE with 1.0%
Croscarmellose sodium
as disperse phase 62 91 95
_
CAPSULE with 2.0~
Croscarmellose sodium
as disperse phase 72 98 100
Example 2
100 parts of a commercial gelatin of 240 Bloom adapted to a
content of 17 % by weight o~ water is intensively mixed with 0.8
parts of a disperse phase material in the form of a dry powder
so that a freely flowing granulate is obtained.
The disperse phase materials are (a) Croscarmellose sodium, (b)
cross linked polyvinylpyrrolidone, (c) carboxymethyl cellulose,
(d) carboxymethyl starch, and (e) microcrystalline cellulose
(Avicel).
The thus produced granulates are then filled into the hopper of
a screw-injection moulding machine, equipped with an 22 mm screw
(L/D ratio: length over diameter ratio: 21, Arburg Allrounder
220-90-350). The processing conditions of this injection moulding
experiment are as follows:
Barrel temperature profile:
Tb: 90 C / Tm: 155 C / Te: 160 C / Tg: 160 C
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17 PD-7038-64-SIL
Screw speed: 250 [rpm]
Injection time: 0.2 seconds
Injection pressure: 1850 bar
Cycle time: 8 seconds
The various gelatin compositions are moulded into capsule cap and
body parts using a mould with eight cavities.
Under these conditions, gelatin capsules of good quality are
obtained under continuous processing, - the capsule parts thus
obtained are not soft and keep their shape unchanged upon
storage.
Very good in vitro dissolution characteristics are obtained
which are superior to those obtained from capsules produced
without the addition of a disperse phase material.
Example 3
-Example 2 is repeated wi~h a gelatin of 240 Bloom and a water
content of 15 % by weight. To 100 parts of this gelatin 0.85
parts of the disperse phase materials and 0.5 parts of magnesium
stearate are added and well mixed so that a free flowing
granulate is obtained.
The processing conditions are as follows:
Barrel temperature profile:
Tf: 90 C / Tm: 155 C / Te: 160 C / Tg: 160 C
Screw speed: 250 [rpm]
Injection time: 0.2 seconds
Injection pressure: 1800 ~bar]
Cycle time: 8 seconds
The same mould is us~d as in Example 2. Under these condi~ions,
and under continuous processing, precision gelatin capsules of
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18 Pl)-7038-64-SIL
excellent quality are obtained. Capsule bodies are not soft and
keep their shape unchanged upon storage.
Very good in vitro dissolution charactexistics are obtained.
Example 4
100 parts of a commercial gelatin of 200 Bloom and with a water
content of 12 % are mix~d with 8 parts of glycerol and 1 part of
disperse phase material (as in example 2) and the various gelatin
mixtures are fed into an injection moulding machine to produce
hard gelatin capsule body parts as described in Example 2.
The processing conditions are as follows:
Barrel temperature profile:
Tf: 90 C / Tm: 120 C / Te: 130 C / Tg: 130 C
Screw speed: 250 [rpm]
Injection time: 0.2 seconds
Injection pressure: 1500 [bar3
Cycle time: 8 seconds
The same mould is used as in Example 2. Under these conditions,
and under continuous processing gelatin capsules of excellent
quality and dissolution characteristics are obtained.
Example 5
100 parts of a commercial gela~in of 150 Bloom and a water
content of 12 % are mixed with 10 parts of glycerol, 2 parts of
disperse phase material (as in Example 1) and injection moulded
to produce hard gelatin capsule parts as described in Example 3.
The processing conditions are as follows:
Barrel temperature profile:
, ~ .
2 ~
19 PD-7038-64-SIL
Tf: 90 C / Tm: llO C / Te: 120 C / Tg: 120 C
Screw speed: 250 [rpm]
Injection time: 0. 2 seconds
Injection pressure: 1400 [bar
Cycle time: 9 seconds
Under these conditions, and under continuous processing, gelatin
capsules of excellent quality and dissolution characteristics are
obtained.
Example 6
100 parts of a commercial gelatin of 150 Bloom and a water
content of 12 % are fed. into a ~win screw extruder (Type Warner
Pfleiderer) at a rate of 5 kg/hour. At a separate inlet a 10
: 1 mixture of monoglycerinacetate and disperse phase material
is ed into the extruder at a rate of 10 parts per hour.
Temp~ratures are maintained at between 90 C and 105 C.
The solidified melt is granulated,-from which granulate shaped
articles are produced.
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