Note: Descriptions are shown in the official language in which they were submitted.
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COMPACT MEMBER COMPRISING A PLURALITY OF POF;OUS CELLULOSE MATRICES) (PCMs))
METHOD OF
MANUFACTURING AND USE THEREOF
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a compact member having extended release of
an active compound. In particular it relates to a 'tablet based on multiple-
units made of
porous cellulose matrices (PCMs}, and having tile property of at the same time
being
easily handled without being damaged, and having an adequate rate of
disintegration.
The release rate of the active compound is controllable.
BACKGROUND OF THE INVENTION AND PRIOR ART
Simple incorporation of drugs into PCMs (without coating) may retard the drug
release but usually not to an extent sufficient for extended release purposes,
and has
therefore not been commercially feasible.
Extended release of an active compound, e.g. a drug, is possible to achieve by
providing drug-loaded porous beads with a coating, such as a release-
controlling, water
permeable film or membrane. This technique has been extensively used
heretofore in
the art. In the process of forming such films or membranes organic solvents
are often
needed, which from both economic and environmental point of view is
undesirable.
Multiple-unit (MU) preparations containing a plurality of pellets have been
used
as carriers of drugs previously. The use of MU drug preparations is considered
to pro-
mote good absorption properties since they are dispersed over a large area in
the gastro-
intestinal (GI) tract. Furthermore, they are considered to have a lower
transit rate espe-
cially in the colon compared to matrix tablets. In addition, MU preparations
are prefer-
able to single unit preparations, since they may be divided into smaller
portions all
having the same release and absorption properties which will give greater
flexibility in
selection of the dose size. Also, MU preparatior.~s will facilitate
administration of the
drug to patients having problems to swallow and will considerably reduce the
risk of
dose dumping.
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Extended release multiple-units (MUs), based on porous matrices of the type
mentioned above, as carriers of drugs have commonly been filled in hard
gelatine cap-
sules. However, there is an increasing interest in the compaction of extended
release
multiple-units into disintegrating tablets. The reason for this is the
advantages of tablets
over the above mentioned capsules, such as more rational production, higher
dose accu-
racy and lower risk of tampering. Unfortunately the release rate is often
affected by
compaction. The release rate may increase due to crushing, formation of cracks
in the
release-controlling coating etc., or decrease due to complete or partial
failure of tablets
to disintegrate. Tablets made of coated multiple-units with intact or nearly
intact release
rate by the use of relatively large amounts of excipients have been reported.
The func-
tion of the added excipients may be to protect the film by absorbing energy
during com-
paction or to act as disintegrants.
PCMs may e.g. be prepared by a wet or a dry method as disclosed in Internatio-
nal Patent Applications WO-A-91/18590 and WO-A-94/23703, respectively, both
assigned to Pharmacia & Upjohn AB of Sweden. The preparation of PCMs does not
form part of the invention, and will not be specifically discussed herein.
Instead, the said
patent applications are incorporated by reference. PCMs are normally small
spherical
particles, so-called pellets, with a diameter in the range of from about 0.5
up to about
1.5 mm, suitably with a diameter of about 1 mm.
Other methods for making pellets of cellulose, optionally incorporating one or
more additional substances, e.g. lipids, could be extrusion/spheronization,
"layering",
melt-pelletization and spray-cooling.
Extrusion/spheronization is performed by pressing a moistured powder mass
through a metal sheet wherein a plurality of holes has been made. The mass
thereby
forms spaghetti-like threads. These threads are transferred to a horizontally
rotating
plate, where they are broken to pieces and formed to spheres which
subsequently are
allowed to dry.
In "layering", powder and liquid are added to small seeds (commonly sugar),
having been rotated in a so-called pan or the like. Layer by layer, larger
spheres are
built.
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In melt-pelletization, spheres can be formed in a Teflon-coated mixer when
part of the powder melts.
In spray-cooling a melt is comminuted into small droplets that solidify and
form
small spheres.
The above methods are part of the prior art and the skilled man will be able
to
manufacture beads according to any of said routes by virtue of his ordinary
skill.
Porous cellulose matrices (PCMs) have been shown to be potential multiple-unit
(MU) drug carriers (Davidson et al., "Porous cellulose matrices - a novel
excipient for
the formulation of solid dosage forms", Int. J. Pharm. l 00 ( 1993 ) 49-54).
A possible method to modify the drug release rate from non-compacted PCMs is
by incorporating release-modifying substances itogether with the drug into the
pores of
the cellulose matrix, as disclosed in WO-A-91 /1'~ 8590.
If thermoplastic materials could be used as release modifiers, the
incorporation
could be done by making use of such materials in a molten state. It might then
be
possible that the process be carried out without excessive energy input or
organic
solvents. Especially if the drug could be incorporated by suspending it in or
otherwise
mix it with the melted release modifier, this process could be very cost
effective.
Non-compacted PCMs have been shown to extend the release of paracetamol
incorporated together with lipids in the matrix pores. This type of spherical
extended
release pellets could be produced very cost effectively with low energy
consumption
and without any organic solvents. Another possible advantage of this type of
system is
that drug release from matrix pellets of this type; may be less sensitive to
compression
than pellets coated with a thin membrane. It also seems reasonable that the
disintegrating effect of cellulose could be advantageous when trying to
compact PCMs
into disinte-grating multiple-unit tablets.
As mentioned above, MUs are commonly delivered in doses contained in hard
gelatine capsules. It would be desirable to be able to manufacture tablets by
compression of MUs, because manufacture would thereby become more cost
effective,
tablets would be more easily divided in subdosf;s etc. However, MUs are
difficult to
make into tablets by compression since
1 ) tablets made from MUs do not easily disintegrate upon oral administration,
and
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4
2) the MUs are easily crushed or damaged during the compaction process, having
as a
consequence that the release rate is substantially increased.
In order to avoid the above problems the prior art teaches addition of
substantial
amounts of various additives, located between the particles. Such measures add
to the
complexity and cost of the manufacturing process, apart from introducing
unnecessary
chemicals into the medicaments.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide compact members
(tablets)
having extended release of an active compound, said compact members having the
properties of
1 ) being easy to handle without said members being damaged; and
2) rapidly disintegrating in-vivo (in the gastrointestinal tract) e.g. when
administered
orally.
In addition, the above object should be achieved without having to incorporate
large amounts of additives in the compact members.
This object is achieved in one aspect of the invention with a compact member
comprising a plurality of PCMs, and providing extended release of an active
compound
contained therein, as claimed in claim 1.
The advantage of the compact member of the present invention is thus the
combination of
1 ) it being easy to handle in industrial processes, such as packaging etc.,
by virtue of its
low friability, and
2) disintegration times suitable for its intended purpose.
It is a further advantage of the present invention, that the compact members
can
be given an in-vitro dissolution rate which is essentially the same as that
exhibited by
the uncompacted pellets of which the compact member consist. This means that
the
amount of drug released does not deviate more than ~ SO % of the total amount
of drug
in the compact member, at any time.
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The compact member suitably contains talc, as claimed in claim 6. The release
rate may be controlled by varying the talc content. Thereby, the release rate
of the active
compound can be practically equal to the release rate of free PCMs.
Especially it is suited for use in its preferred embodiment as a tablet
containing a
drug, as claimed in claim 12.
In another aspect of the invention there is provided a method of manufacturing
tablets having the desired properties. This is achieved by the method as
defined in claim
14.
In yet another aspect of the invention thc;re is provided use of a compact
member
according to the present invention for administration of a drug, as defined in
claim 20.
The invention will become more fully understood from the following
illustrative
description of preferred embodiments thereof, by way of non-limiting examples,
and
with reference to the appended drawing figures.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a graph showing radial tensile strength for tablets according to the
invention (filled circles) and tablets of empty PCMs (open squares) as a
function of
compaction pressure;
Fig. 2 is a graph showing disintegration time for tablets according to the
invention as a function of compaction pressure;
Fig. 3 is a graph showing release of drug; from pellets not according to the
invention as a function of time for different lipid compositions;
Fig. 4 is a graph showing release of drug; from tablets according to the
invention
as a function of time at two different compaction pressures using two in-vitro
dissolu-
tion methods;
Fig. 5 is a graph showing release of drug for tablets according to the
invention as
a function of time at five different compaction pressures and for uncompacted
pellets;
Fig. 6 is a graph showing the effect of talc on release of drug of a tablet
according to the invention (tablet of granules arid 5 % (w/w) talc (open
triangles),
tablets without any talc (filled circles)) and uncompressed granules as a
reference (X).
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DETAILED DESCRIPTION OF THE INVENTION
Drug release from PCMs has, as mentioned above, been shown to be possible to
extend over at least 16 hours by incorporating release modifiers together with
the drug
into the pores in the cellulose matrix. The rate of release could be adjusted
by varying
the release modifier composition, drug concentration and particle size of the
PCMs. The
release seems to be controlled by diffusion from the matrix but is also
affected by the
distribution of drug in the matrices and an increase of porosity due to
erosion of matrix
material and pores formed by the swelling of cellulose. The incorporation of
drug and
release modifier could be performed simultaneously by dispersing a micronized
drug
into the molten release modifiers. Hence, an extended release multiple-unit
preparation
may be prepared from PCMs with a simple, solvent-free, one-step process.
Materials suitable as release-modifying agents are characterized by exhibiting
a
low melting point, a low viscosity above the melting point and a low
solubility in water.
The material is suitably only slightly soluble in water and preferably
insoluble in water.
Lipids may be suitable as release modifiers for incorporation into PCMs, since
they are often low-melting, non-toxic, relatively inexpensive and there is a
broad range
of lipids with different physico-chemical properties.
Lipids may be classified on the basis of their different interaction with
water into
non-polar lipids (e.g. aliphatic hydrocarbons) and polar lipids. The polar
lipids could be
further subdivided into different classes: I) insoluble nonswelling
amphiphilic lipids, II)
insoluble swelling amphiphilic lipids and III) soluble amphiphilic lipids,
where the
solubility refers to water as a medium.
The release rate from lipophilic matrices can often be controlled by the use
of a
mixture of a nonpolar and a polar lipid or of two polar lipids from different
classes.
There is no universal definition of "lipid". Lipids are sometimes defined as
naturally occurring fats, oils and waxes: However, here the word lipid is used
in a
broader sense covering also e.g. aliphatic hydrocarbons and fatty alcohols.
Examples of
lipids which have been used as meltable excipients are fatty acids, e.g.
stearic acid, long
chain alcohols, e.g. cetostearyl alcohol, naturally occurring and synthetic
waxes,
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glyceryl esters of fatty acids, e.g giyceryl monostearate, glyceryl
distearate, or glyceryl
tristearate, aliphatic hydrocarbons, e.g. hard paraffin, polyglycerol esters
of fatty acids,
and any mixture thereof.
In the present invention, it is advantageous to use a release-modifying agent,
preferably a lipid, with a melting point in the range of from about
10°C up to about
200°C, suitably from 20°C up to 150°C, and preferably
30°C up to 100°C.
Prior to compaction, small amounts of adiditives may be added to the PCMs to
give the resulting compact members specific properties as regards release
rate, tensile
strength etc. Thus, the compact members may contain up to about 10 %, and
preferably
up to 5 % by weight of talc. Also, the compact members may contain up to about
5 %,
suitably up to about 1 %, and preferably up to O.S % by weight of a lubricant.
Suitably,
use is made of magnesium stearate, which is a conventional and economic
choice.
In the present invention, the PCMs can be made from a wide variety of
cellulose
raw materials. Suitably, the cellulose raw material is substantially pure,
preferably of a
pharmaceutical purity grade. It is also conceivable to use one or more
chemically
modified derivatives of cellulose as raw material, such as carboxy
methylcellulose
(CMC), alkylcelluloses, e.g. methylcellulose or f;thylcellulose,
hydroxypropylcellulose
(HPC) or alkyl hydroxyalkyl celluloses, e.g. ethyl hydroxyethylcellulose
(EHEC),
optionally in any mixture with cellulose.
In manufacturing of the compact members according to the present method, the
release-modifying agent is incorporated in the pores of the PCMs by any method
suitable for the release-modifying agent at issue. For example with lipids, a
melt process
would be preferable, i.e. the lipid would be meltf:d before incorporation.
The active compounds contained in the compact members of the present inven-
tion, are preferably drugs (pharmaceuticals). The: present invention is
suitable for hydro-
philic drugs, i.e. drugs soluble in water or aqueous solutions. Furthermore,
the present
invention is particularly useful for drugs exhibiting a biological half life
of less than
about 20 hours, since extended release of drugs with a longer biological half
life is
normally not necessary. The present invention is preferably used for drugs
exhibiting a
biological half life of less than 15 hours, and more preferably less than 10
hours.
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It should be recognized that the active compound to be incorporated in the com-
pact members of the present invention may be any of a number of different
compounds
for different uses apart from drugs, e.g. fertilizers, pesticides, herbicides
etc.
The compact members of the present invention may contain up to about 50 % by
weight of the active compound, suitably up to 10 %, and preferably up to 2.5 %
by
weight of the active compound.
In manufacturing of the compact members according to the present method, the
PCMs can be exposed to the active compound and release-modifying agent in
optional
order, or preferably simultaneously, after premixing of the active compound
and release-
modifying agent. The active compound and release-modifying agent can be dry
mixed,
as disclosed in Example 1 of the present specification. Other types of mixing
are con-
ceivable, and for the purpose of this invention, the term mixing would
encompass any
form of dispersing, suspending, emulsifying etc. which reasonably
homogeneously
would distribute the active compound in a release-modifying agent.
In order not to obtain unacceptable agglomeration of individual PCMs because
of an excess of active compound and release-modifying agent present, the
amount of
active compound and release-modifying agent necessary to fill the pores to a
preselected
level for a given batch, is calculated from the densities of the active
compound and
release-modifying agent and the known pore volume for a given amount of PCMs.
The
porosity of pure PCMs can be calculated from pellet density data measured by
mercury
porosimetry and from apparent density data obtained by helium pycnometry. In
the
present invention, it is suitable that the pores are filled with the active
compound and
release-modifying agent to at least about 50% of the pore volume, preferably
at least
70%, and more preferably at least 80% of the pore volume, before compacting
the
PCMs.
In manufacturing of the compact members according to the present method, the
PCMs comprising an active compound and a release-modifying agent are compacted
to
a desired shape. Examples of desired shapes of compact members are
cylindrical, cylin-
drical with rounded upper and lower surfaces, cubical and essentially
spherical.
In manufacturing of the compact members according to the present method, the
pressure in the compacting step is suitably less than about 500 MPa,
preferably in the
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range of from 10 up to 200 MPa, and more preferably in the range of from 50 up
to 150
MPa.
From a medical point of view it is desirable that compact members, such as tab-
lets, exhibit disintegration times in-vitro of less khan about 240 minutes.
The disintegra-
tion time in-vitro is suitably less than 90 minutes, and preferably less than
60 minutes.
Radial tensile strength is an important property for the compact members of
the
invention, since the radial tensile strength is a measure of the cohesive
properties of the
compact members, e.g. tablets. The radial tensile: strength of the compact
member of the
present invention can be higher than about 0.1 NfPa, suitably higher than 0.3
MPa, and
preferably higher than 0.5 MPa.
EXPERIMENTAL
The following Examples are provided for purposes of illustration only and are
not to be construed as in any way limiting the scope of the present invention,
which is
defined by the appended claims.
The percentages and parts are per weight., unless otherwise stated.
Example 1 not according to the invention)
A multiple-unit extended release matrix preparation, was prepared by the
incorporation of a hydrophilic drug (Paracetamo:l; Hoechst, Germany) and
lipophilic
release modifiers (Cetanol; Bionord AB, Sweden, and hard paraffin; MB Sveda,
Sweden) into porous cellulose matrices (PCMs).
The PCMs were made according to the rr.~ethod disclosed in WO-A-94/23703.
The drug was micronized and dry mixed with a lipid, using a mortar and a
pestle. The
drug and lipid mixture was then heated on a water bath and the drug was
thereby
dispersed substantially homogeneously in the molten lipid. PCMs were added
during
stirring. It is also conceivable to add the drug to the molten lipid, or vice
versa. The
mixtures were allowed to cool during stirring. The size fractions 0. S - 0.71,
0.71 - 1.2
and 1.2 - 1.4 mm were obtained by sieving. Two pellets with no cellulose were
also
prepared for comparison. The various formulations are shown in Table 1.
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TABLE 1
Prepared pellets and results from linear regression of ln(released drug) vs
ln(time) for <60% drug released for studied pellets. Lipid concentration is 43
% (w/w)
5 unless otherwise indicated.
Lipid composition. Paracetamol Particle size Drug particle
(paraffin:cetanol) content (mm) size (gym)
(% w/w)
(% w/w)
1:0 2.5 0.7-1.2 2.2
l:l 2.5 0.7-1.2 2.2
1:2 2.5 0.7-1.2 2.2
1:3 2.5 0.7-1.2 2.2
0:1 2.5 0.7-1.2 2.2
1:2 (40% lipid) 2.5 0.7-1.2 2.2
1:2 (37% lipid) 2.5 0.7-1.2 2.2
1:2 2.5 0.5-0.7 2.2
1:2 2.5 1.2-1.4 2.2
1:2 2.5 0.7-1.2 3.4
1:2 2.5 0.7-1.2 8.4
1:2 1 0.7-1.2 2.2
1:2 5 0.7-1.2 2.2
The amounts of drug incorporated into PCMs were assayed spectrophoto-
metrically after extraction in ethanol (95%).
The release rates were determined according to USP method I (basket) in
distilled water, at 37°C, 100 rpm. The amount released was detected
spectrophoto-
metrically (~,=244 nm). The amount of pellets was chosen in order to maintain
sink
condition during the entire release measurement and to get optimal analytical
sensitivity. The results are shown in Fig. 3 as release of drug vs time for
PCMs loaded
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with various lipid compositions. In Fig. 3 filled squares represent PCM and
pure hard
paraffin, filled triangles represent PCM and 1:1 of hard paraffin:cetanol,
filled circles
represent PCM and 1:2 of hard paraffin:cetanol, empty triangles represent PCM
and 1:3
of hard paraffin:cetanol, empty squares represent PCM and pure cetanol, and
empty
circles represent reference pellets without cellulose matrix, i.e. pure lipid.
As can be seen in the figure, the in-vitro drug release could be extended over
at
least 16 hours. The release rate could be controlled by varying the ratio of
cetanol to
paraffin.
Example 2 (according to the invention)
The possibility to compact PCMs into disintegrating extended release multiple-
unit tablets was studied using a hydrophilic drug; and lipophilic release
modifiers.
Paracetamol (Hoechst, Germany) was chosen as a model drug substance since it
is relatively stable and non-toxic and since it has been used in earlier
studies.
Cetanol (Bionord AB, Sweden) and hard. paraffin (MB Sveda, Sweden) was used
as release-modifying lipids.
Magnesium stearate (Kebo, Sweden) was used as model lubricant.
Anhydrous silicon dioxide (Aerosil, Degussa AG, Germany) and talc (Kebo,
Sweden) were used as anti-adherents.
PCMs were manufactured from cellulose: using a special process involving
mechanical treatment in the presence of water (~JJO 94/23703). The size
fraction 0.71-
1.17 mm was obtained by sieving.
Paracetamol and drug-and-lipid mixtures were incorporated into PCMs by the
melting procedure as described in Example 1. The composition used contains 54
(w/w) cellulose, 43 % (w/w) lipid (cetanol: paraffin 2:1 ) and 2.5 % (w/w)
paracetamol.
The loading was performed in subbatches of 151) g. Five subbatches were then
poured
into a polyethylene bag and mixed by hand shal<;ing.
The porosity of pure PCMs was determined to be 54%. The porosity was calcu-
lated from pellet density data measured by mercury porosimetry and from
apparent
density data obtained by helium pycnometry.
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Some of the drug-and-lipid loaded PCMs were mixed, for 60 minutes, with
magnesium stearate, talc and/or anhydrous silicon dioxide in a Turbula Mixer
(2 liters,
W. A. Bachofen, Switzerland). The batch size of the mixtures was 50 - 100 g.
A11 materials were stored for no less than 48 hours at 40 % relative humidity
and
room temperature (20-25°C) before compaction. Loaded and empty PCMs
were
compressed to tablets, at 12 (~ 1), 20 (~ 1), 35 (~ 2), 50 (~ 2), 75 (~ 2),
100 (~ 5) and 200
(t 5) MPa in a single punch press (Korsch EKO, Korsch, Germany). Flat faced
punches
with a diameter of 11.3 mm were used. The shortest distance between the
punches was
set to 3 mm. The particles for each tablet were weighed and poured manually
into the
die. A suspension of 1 % magnesium stearate in ethanol (95 %) was used as an
external
lubricant. The tablets were kept at 40 % relative humidity and room
temperature (20-
25°C) for at least 48 hours, before characterization.
Tensile Strength
The diametrical crushing force was measured in a tablet hardness tester (C 50,
Holland Ltd., UK). Radial tensile strength was calculated from diametrical
compression
data according to the method by Fell and Newton (J. Pharm. Pharmacol., 20
(l968) 652-
659). The results are shown in Table 2a for 12 MPa and 200 MPa pressures,
respecti-
vely. The results are shown also in Fig. 1 which shows radial tensile strength
vs. com-
paction pressure for tablets of PCMs with incorporated drug and lipids and
unloaded
PCMs. In Fig. 1, filled circles represent PCMs loaded with drug and lipid, and
squares
represent unloaded PCMs.
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TABLE 2A
Tensile strengths for pellets compressed at 12 and 200 MPa, respectively, with
and without some additives.
Additives Radial tensile strength (MPa)
Compressed at Compressed at
12 MPa 200 MPa
No additives 0.16 0.63
1 % Mg stearate 0.14 0.64
5% talc 0.11 0.49
5% colloidal silicon
dioxide 0.094 0.53
5% colloidal silicon
dioxide and 1
magnesium stearate 0.064 0.68
With reference to Fig. 1, surprisingly it was found that the incorporation of
drug
and lipid increases the compactability of the PCIvIs at low pressures, so that
coherent
tablets are obtained already at 12 MPa, whereby the tensile strength is above
0.1 MPa.
The tensile strength increases approximately linearly with compaction pressure
for
empty PCMs. For drug-and-lipid PCMs, a const;~nt tensile strength is obtained
for
pressures above 50 MPa. The increased tensile strength at low pressures of
drug-and-
lipid PCMs is probably due to the high ductility of the lipid mixture. That a
lipid, added
before compression by a melt method, may increase the tensile strength of
tablets has
been shown for stearic acid. The constant tensile strength at compaction
pressures above
50 MPa could be due to the fact that no further deformation of the lipid is
possible and
that bonds have formed through all lipid material in the tablet. Some
adherence of lipid
material to the punch faces support the idea/suspicion that bonds may form due
to par-
tial melting or advanced diffusion during compaction. The assumption that
bonds may
have been formed is also supported by the low melting point of the lipids:
49.5°C for
cetanol and 50 - 62°C for hard paraffin. Another explanation for the
constant tensile
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14
strength above 50 MPa could be the fact that increased elastic expansion is
cancelling
out the effect of an increased volume reduction. The lipids appear to act as
lubricants. It
is not absolutely necessary to add magnesium stearate for the tablets to be
ejected from
the die. However, an antiadhesion agent may be needed in some instances.
Friability
For the purposes of this invention the friability of a compact member of the
invention is defined as the amount of material attrited in a friabilator
according to the
procedure described below.
The friability of the tablets was measured in a friabilator model TA3 (Erweka
Apparatebau, Germany). A pre-weighed sample of 10 tablets was rotated for I00
turns
at a speed of 25 rpm and the amount of attrited material was determined
gravimetrically.
The friability expressed as a percentage was then calculated, and shown in
Table 2b.
I S TABLE 2B
Friability values for pellets compressed at 12 and 200 MPa, respectively, with
and without some additives.
Additives Friability (%)
Compressed at Compressed at
12 MPa 200 MPa
No additives 2.1 0.27
1 % magnesium stearate 8.0 0.30
5% talc 14 0.09
5% colloidal silicon
dioxide 100 ~ 0.3 8
5% colloidal silicon
dioxide and 1
magnesium stearate 100' 0.l4
~ All tablet fragments were smaller than a half tablet after friability test
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As can be seen from Table 2b, all tablets compressed at 200 MPa exhibit
friability values well below 0.5 %, and even at 12 MPa tablets without any
additives
exhibit friabilities of no more than 2.1 %. For industrial applications and
handling, it is
5 desirable that the friability is less than 1 %, although for certain
applications higher
friabilities may be acceptable.
Friction Properties
For evaluation of the friction, PCMs and mixtures of PCMs with additives was
10 tableted in the single punch press at 12 and 200 IVIPa (~ 10 %) with
automatic feeding
and at a rate of approx. 37 tablets/minute. At least 25 tablets were
compressed until
constant ejection forces were obtained. The maximum upper and lower punch
pressures
and the ejection forces were then recorded for 10 tablets. The mean height of
the tablets
were measured after compression. The difference: between maximum upper and
lower
15 punch pressures per tablet area in contact with th.e die (FD/A) and the
ejection force per
tablet area in contact with the die (Ej F/A) were tlhen calculated. These have
been
suggested as the most useful parameters for the study of friction during
compaction.
The height of the tablets after ejection was used .as an estimate of height of
the tablet in
the die.
Table 3 shows the results of the evaluation of friction characteristics for
different
formulations.
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16
TABLE 3
Friction characteristics and observed adhesion for pellets compressed at 12
and
200 MPa, respectively, with and without some additives.
EjF/A FD/A (kN/cm2) Observed
(kN/cm2)
adhesion
Additives Compre ssed at Compressed (severe/
at
12 MPa 200 MPa 12 MPa 200 MPa moderate/
no)
No additives 0.068' 0.098' 0.l01 0.04 severe
1 % magnesium
stearate 0.047' 0.098' 0.095 0.221 moderate
5 % talc 0.068' 0.080' 0.106 0.304 no
5 % colloidal silicon
dioxide 0.297 0.3l3 0.280 0.7l2 no
5 % colloidal silicon
dioxide and 1
magnesium stearate0.137 0.153 0.192 0.638 no
' The ejection forces were not significantly distinguishable from the
background inter-
ference
Disintegration
The disintegration time in deionized water was measured in an Erweka ZT 3
(Erweka Apparatebau, Germany) according to the USP method with discs.
The in-vitro drug release rates were determined according to USP method II
(paddle) in deionized water, at 37°C with spectrophotometric detection.
The stirring
speed was 200 rpm. The USP method II (paddle) was used since preliminary
trials
showed that the tablets did not disintegrate if USP method I (basket) was
used. How-
ever, in order to study the effect of tablet disintegration on drug release
some tests using
the basket method at 100 rpm were performed. One tablet or approximately 360
mg
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17
pellets were added to each vessel with 900 ml water. This amount was chosen in
order
to maintain sink condition during the experiment.
Mean disintegration times were measured (Table 2c and Fig. 2), and was shown
to be affected by compaction pressure. Thus, they vary between 8 and 120
minutes for
S PCMs without additives and between 6 and 65 minutes for PCMs with additives
such as
talc, magnesium stearate and/or colloidal silicon dioxide.
TABLE 2C
Disintegration times for pellets compressed at 12 and 200 MPa, respectively,
with and without some additives.
Additives Mean disintegration times (min)
Compressed at Compressed at
12 MPa 200 MPa
No additives 8 34
1 % magnesium stearate 9 b5
5 % talc 6 19
5 % colloidal silicon
dioxide 9 29
5 % colloidal silicon
dioxide and 1
magnesium stearate 7 25
From a medical point of view it is desirable that tablets exhibit
disintegration
times of less than about 240 minutes, and thus the tablets are well suited for
their
intended purpose. A maximum was observed at ',15 MPa, and at higher and lower
compaction pressures respectively, disintegration times were shorter. The
decrease of
disintegration time at compaction pressures above 75 MPa may be due to the
cellulose
fibres from different pellets getting into closer contact at higher pressures.
Hence, more
strain is caused by their swelling. Tablets made from unloaded PCMs
disintegrated
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18
within less than 3 seconds irrespective of compaction pressure, demonstrating
the good
disintegrating effect of PCMs. Some small agglomerates of approximately 2-5
pellets
could be observed also after disintegration of the tablets for drug-and-lipid
PCMs but
not for unloaded PCMs.
The tablets did not disintegrate when subjected to 100 rpm in the USP
apparatus
I (basket) as they did in the USP apparatus II (paddle) at 200 rpm (USP method
II at 100
rpm caused a partial disintegration). After having been subjected to the
basket method
for 16 hours the tablets were still coherent although soft and swollen. The
swollen
tablets disintegrated immediately when gently pressed between the thumb and
the index
finger, indicating that in-vivo disintegration is probable.
Interestingly, there was no difference in drug release rate between the two
diffe-
rent methods, indicating that the drug release is independent of tablet
disintegration. The
effect on release rate of compaction pressure and thus disintegration time, is
shown in
Fig. 4, by comparing the release rates using the two methods USP I (basket) at
100 rpm,
and USP II (paddle) at 200 rpm. In Fig. 4 circles represent tablets compressed
at 12 MPa
and tested in USP apparatus II (filled circles), and the same tablets tested
in USP appa-
ratus I (empty circles), respectively. Squares represent tablets compressed at
200 MPa
and tested in USP apparatus II (filled) and USP apparatus I (empty),
respectively.
Without wishing to be bound by any theory, it is believed that the reason for
this
may be that pores are rapidly formed between the pellets when the cellulose
swells and
that the transport in these pores is so rapid that only the diffusion in the
pellets will
control the release rate. The bonds keeping the swollen tablet coherent may be
working
over a surface area which is negligible compared to the exposed surface area
of the
pellets. Hence, the breaking of the bonds does not influence the drug release
rate.
However, there may still be bonds over larger surface areas, forming small
agglomerates
of pellets. These bonds may influence the release rate but they are not
necessarily
broken during the disintegration of the tablet but may remain unchanged
throughout the
dissolution process.
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19
D~Release
The drug release from tablets compacted .at 12 MPa was faster than from uncom-
pressed pellets. The increase in release rate at 20 MPa was less and at 3 5
MPa the
release was slower than for uncompacted pellets. Further increase in the
compaction
S pressure increased the release rate only to a small extent. This is shown in
Fig. 5
wherein release rates for tablets compressed at various pressures are shown as
a function
of time. The tests were performed using the USP II method at 200 rpm. In Fig.
5, empty
circles and empty triangles represent tablets compressed at 12 MPa and 20 MPa,
respec-
tively. Empty squares and filled squares represent tablets compressed at 35
MPa and
100 MPa, respectively. Filled circles and filled triangles represent tablets
compressed at
200 MPa and uncompressed pellets, respectively.
Again without wishing to be bound by any specific theory, it is possible that
the
increase in release rate at low pressures may be due to some lipid being
squeezed out of
the PCMs during compression, increasing the porosity and surface area of the
pellets. At
higher compaction pressures, lipid may be squeezed back into the pores of the
PCMs. In
this process, some of the drug is redistributed and less drug may be exposed
at the surfa-
ces of the PCMs. It has been shown that the incorporation process may cause a
higher
drug concentration close to the surface of the PC:Ms than in the centre of the
matrices. It
is also possible that higher compaction pressures may increase the number of
small agg-
lomerates of spheres, which do not deagglomerat:e upon tablet disintegration.
Conse-
quently, the surface area of the matrices will decrease.
For pure pellets or mixtures with magnesiium stearate or talc, the lower punch
forces detected during the ejection were not signiificantly different from the
background
reference (Table 3). When colloidal silicon dioxide was added the ejection
force (EjF)
increased. An addition of 1 % magnesium stearal:e to the silicon dioxide
mixture
decreased the ejection force somewhat. As expected, FD/A values were low for
pure
pellets compacted at both 12 and 200 MPa. Addition of magnesium stearate or
talc did
not increase FD/A. Colloidal silicon dioxide, on the other hand, increased
FD/A. This
indicates that no lubricant is needed for the tableting of extended release
pellets prepa-
red by the incorporation of lipid release modifiers into PCMs. However, since
some
adherence to punch faces was seen, addition of an antiadherent may be
necessary. If so,
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talc gives better friction properties than colloidal silicon dioxide when
added at the same
concentration.
Addition of excipients (magnesium stearate, talc and/or colloidal silicon
dioxide)
decreased the tensile strength of the tablets compacted at 12 MPa (Table 2a).
5 For tablets compressed at 200 MPa the effect of additions of excipients on
tensile strength was small. It is contemplated, without knowing the exact
mechanism,
that the lack of effect of excipients on tensile strength at higher compaction
pressure
may be due to the high ductility of the lipids, which means that the lipids
could flow
around the excipient particles and create bonds around them. It is well known
that a
10 high tendency of a substance to fragment during compaction will counteract
the tensile
strength, lowering effect of magnesium stearate. However, it seems reasonable
that
extreme ductility may have the same effect. Extreme deformation of a substance
will
lead to redistribution of the magnesium stearate covering its surfaces.
The effect on disintegration times of the added excipients was low at 12 MPa.
At
15 200 MPa the disintegration time was increased by magnesium stearate and
decreased by
talc. The increase in disintegration time, when magnesium stearate is added,
is expected
due to the hydrophobic nature of this substance while an explanation for the
decrease
seen when talc is added is less obvious.
The friability of tablets with no additives and compressed at 12 MPa was 2.1
%.
20 Addition of excipients (especially colloidal silicon dioxide) increased the
friability
considerably. At 200 MPa the friability of pure pellets and a11 investigated
mixtures was
below 0.5 % which indicates a sufficient tablet strength for industrial
handling.
Addition of magnesium stearate and talc did not affect the release rate from
tablets compressed at 12 MPa. A small increase in the release rate was seen
when
colloidal silicon dioxide was added. At 200 MPa a11 additions gave an increase
of the
release rate. The increase in the release rate was highest for 5 % colloidal
silicon dioxide
and 5 % colloidal silicon dioxide + 1 % magnesium stearate. The increase was
smaller
when 1 % magnesium stearate was added. For all three mixtures containing
silicon
dioxide and/or magnesium stearate, the release rate was faster than from the
uncompressed pellets. The release from tablets without additives was slower
than from
uncompressed pellets.
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WO 98I20858 PCT1SE97/01901
21
Surprisingly, the release rate from tablets containing an active drug
(paraceta-
mol), with and without added talc (5 % w/w) was approximately the same as from
uncompressed pellets. This effect is shown in Fig. 6, wherein filled circles
represent
tablets without talc and compressed at 200 MPa. Empty triangles represent
tablets with
talc and compressed at 200 MPa. Crosses represent uncompressed pellets without
talc.
This suggests that it is possible to produce extended release multiple-unit
tablets from
drug-and-lipid PCMs with only a small amount of additives.
The higher release rate in the presence of additives may be due to the added
substances forming a coating layer around the pellets. This coating layer may
then either
prevent the formation of non-disintegrating agglomerates or influence the
redistribution
of drug particles during compression. Another possible explanation for the
increased
release rate is that hydrophilic additives are pressed into the matrix pellets
thereby
increasing their hydrophilicity. This may be a possible mechanism for silicon
dioxide
but seems less probable for talc and magnesium stearate.
Thus, in accordance with the invention, extended release matrix pellets
prepared
by incorporation of release modifiers, especially lipids, into PCMs can be
compacted
into disintegrating tablets without the addition of any excipients. The
release rate is
increasing at low compaction pressures and decreasing at higher pressures. By
addition
of 5 % talc it is possible to achieve the same release profile from tablets
compacted at
200 MPa as from uncompacted pellets. The disintegration times appear to be
relatively
long at higher pressures but on the other hand, dmg release appears to be
independent of
tablet disintegration. The pellets seem to be self lubricating although an
addition of
aritiadherent may be necessary.
