Manufacturing matrices

Porous cellulose matrices with a defined particle size and a significantly higher porosity (i.e. pore volume) than conventional formulations, such as pellet formulations containing cellulose and binders are prepared. The cellulose is mechanically treated with low adhesion to the process equipment during a controlled gradual addition of an aqueous based fluid, optionally containing a surface-active ingredient, into regular particles, which are finally dried to obtain dry porous cellulose matrices. The so obtained matrices can be used as carriers for bioactive substances in multiple-unit preparations or tablets.

This application has been filed under 35 USC 371 as the national stage of 
international application PCT/SE94/00331, filed Apr. 14, 1994. 
FIELD OF INVENTION 
The present invention relates to a manufacturing process for multiple unit 
carriers and release controlling systems for bioactive substances from a 
wide variety of cellulose raw materials. It is also directed to the 
manufacture of additives to be used in tablet formation, especially in 
direct compression and to obtain multiple unit preparations in the form 
compressed and disintegrating tablets. 
BACKGROUND OF THE INVENTION 
The background of the present invention is previously disclosed in the 
international patent application WO 91/18590, published 12 Dec. 1991, 
which application also is referred to for a prior art review. 
WO 91/18590 discloses a process for the manufacture of porous cellulose 
matrice particles, which have regular shape, and a capacity of sorbing 
1.5-9 times of their own weight of water, a tap bulk density of less than 
0.85 g/ml. The process for the manufacture of these porous cellulose 
matrices were performed by a mechanical treatment of hydrolyzed cellulose 
in a wet stage. The cellulose matrices preferably have a size of at least 
0.1 mm and a tap bulk density of 0.1-0.7 g/ml. 
According to this patent specification the bioactive substance or bioactive 
substances can be sorbed, precipitated or sublimized into the porous 
structure of the matrices. The matrices can also be admixed with bioactive 
substances or granules containing bioactive substances in order to improve 
the tabletting and tablet properties and thereafter compressed. 
The manufacturing process according to this earlier patent application was 
found to give excellent results for wet hydrolyzed cellulose raw materials 
with suitable plastic properties. It was found possible to obtain 
reproducible properties of the porous matrices by controlling the 
hydrolysis and the mechanical treatment process. Commercial qualities of 
microcrystalline cellulose such as Avicel (FMC Corp), Emocel (Finn Sugar, 
Finland) and Dynacel (Cellupharm AB, Sweden) were found to give more dense 
particles, less suitable in many applications. Furthermore, it was found 
that the use of established microcrystalline cellulose qualities led to 
unacceptable differences in form, size and size distribution. 
However, this manufacturing previously disclosed process is limited to wet 
celluloses subjected to chemical hydrolyzation, which is a disadvantageous 
restriction in the choice of raw materials. The use of wet hydrolysed 
cellulose is also connected with problems related to bacterial growth, 
especially in cases when the cellulose is not subjected to immediate 
processing. Furthermore, the hydrolysis process can be difficult to stop 
before it has reached the levelling off degree of polymerisation, at which 
stage the processed batch essentially contains microcrystalline cellulose. 
The process according to WO 91/18590 is preferably performed by a 
mechanical treatment followed by a forming step in a cyclone. Such a 
process is satisfying in a large-scale industrial context, but it will be 
less suitable for a production in a smaller scale. Therefore a demand 
exists for a process for preparation of the porous cellulose matrices in a 
smaller and more convenient units like high shear mixers. 
In the former process disclosed in WO 91/18590 there is no method adviced 
for drying the cellulose particles. The drying shrinkage has been noticed 
as a problem when loading the matrice particles with an agent dissolved in 
a liquid, which does not re-expand the particles by swelling. 
A problem related to the drying shrinkage is that a film coating on the 
matrice particle may burst when the particle re-expands in contact with an 
aqueous fluid. 
It is the object of the present invention to provide a process which 
overcomes the above mentioned problems as well as satisfying the demand of 
being applicable on a wide variety of raw materials. 
DESCRIPTION OF THE INVENTION 
The present invention is directed to the process for the manufacture of 
porous cellulose matrices with a defined particle size and a significantly 
higher porosity (i.e. pore volume) than conventional formulations, such as 
pellet formulations containing cellulose and binders. The process is 
applicable on a wide variety of substantially dry and preferably pure 
cellulose raw materials, e.g. as disclosed in British Pharmacopoeia 1993, 
vol. 1, Effective date: 1 Dec. 1993, London: HMSO, p. 119-120. The 
cellulose is mechanically treated with low adhesion to the process 
equipment during a controlled gradual addition of an aqueous-based fluid, 
optionally containing a surface-active ingredient, into regular particles, 
which are finally dried to obtain dry porous cellulose matrices. 
The so obtained matrices can be loaded with one or several bioactive 
substance or substances and can optionally be incorporated in a suitable 
carrier, such as a gelatine capsule to form a multiple-unit preparation, 
or they can be compressed into tablets, if suitable by the addition of 
tabletting excipients. 
The manufacturing process is based on a simple mechanical treatment of the 
cellulose raw material which is added to a mixing step in a dry or 
substantially dry state. The mechanical treatment is performed in a 
low-adhesion high shear mixer with a controlled, gradual supply of an 
aqueous-based fluid. Low adhesion mixers are constructed with a very 
smooth surface or a surface covered with materials such as PTFE 
(Teflon.RTM., Du Pont, USA), in order to reduce the adhesion, which 
increases the yield of acceptable cellulose particles according to the 
invention. 
An especially preferred type of mixer is a low-adhesion high shear mixer 
with a spraying device, such as an atomizer, for the supply of the 
aqueous-based fluid. A suitable type of mixer is the Pellmixer from Niro 
A/S, Denmark. 
It is possible to precede the said treatment step with a pre-mixing step of 
cellulose and an aqueous fluid. The pre-mixing can be performed in 
conventional mixing devices, such as a planetary mixer. The mixed batch is 
thereafter charged into the low adhesion mixing device for completing the 
mechanical treatment. 
After completing the mechanical treatment the batch of produced cellulose 
matrices will pass a drying procedure. The drying can be performed with 
standard equipment, for example on trays in an oven at a moderately 
elevated temperature, by a rotary evaporator, in fluidized beds, and by 
means of microwaves. The pressure during the drying processes can be 
atmospheric or reduced. 
A suitable drying procedure according to the invention is freeze-drying. It 
is notable that the matrices, which are freeze-dried, do not shrink to the 
same extent as matrices subjected to other drying procedures. A 
freeze-drying procedure also increases the matrice porosity and maintains 
the roundness of the matrice particles. The general teachings of 
freeze-drying of cellulose webs for increasing the porosity disclosed in 
J. Japan Wood Res. Soc. Vol. 25, No. 6, 1979, p. 414-21 ( T. Yamauchi et. 
al.) are applicable on the inventive matrices. 
The aqueous-based fluid supplied during the manufacturing process is added 
in a total amount 80-500% of the dry weight of the cellulose material and 
can be mixed with another solvent such as ethanol. 
An addition of an alcohol, such as ethanol, in the process fluid will also 
increase the matrice porosity by decreasing the contracting surface 
tension forces and by limiting or completely avoiding hydration of the 
cellulose fibres. An addition of a surface-active agent in the 
aqueous-based fluid can also reduce the shrinking of the matrices during 
the drying procedure due to a reduced surface tension in the aqueous 
medium. 
Suitable surface-active agents are polyoxyethylene sorbitan fatty acid 
esters (Tweens), but anyone skilled in the technique will have no problems 
to find alternative agents. 
It must be emphasised that there are applications where the aforedescribed 
re-expanding by swelling in water contact phenomenon is advantageous. For 
example a delivery of an initial release of a bioactive substance to an 
aqueous medium can be accomplished if a certain fraction of multiple unit 
are designed to burst in water contact. Another way of using the swelling 
properties of the matrices is to include a certain fraction of highly 
swelling matrices in a population of matrices which are compressed to a 
tablet in order to disintegrate it in a controlled manner in the 
gastrointestinal tract. It will be within the scope of the present 
invention to use controlled swelling of the matrices as a controlled 
release device for bioactive substances from cellulose matrices, to 
include a certain amount of such bursting particles in a population of 
multiple units and to use such matrices as disintegrating means in a 
tablet. 
The variation of process parameters, such as impeller speed, the supply 
rate and the composition of the aqueous mixing fluid will have influence 
on the product quality of the porous cellulose matrices. Any such 
parameter variations will, however, be easy for a person skilled in the 
art to identify and to utilize the advantages thereof, and it is to be 
considered that any such modifications of the process is covered by the 
appended patent claims. 
It is notable that the inventive process can produce the cellulose matrices 
with the desired properties from a wide variety of dry cellulose raw 
materials, preferably of other sources than chemically hydrolyzed 
celluloses. Suitably, the cellulose raw material is substantially pure, 
preferably of a pharmaceutical purity grade. It is also conceivable to use 
one or more derivatives of cellulose as raw materials, such as carboxy 
methylcellulose (CMC), optionally in any mixture with cellulose. 
A suitable type of cellulose raw material is SOLKA-FLOC.TM. (Mendell, USA), 
but also the dry fibrous materials disclosed in the patent specification 
U.S. Pat. No. 4,464,224, column 4, lines 4-10 are considered as suitable 
alternatives. When choosing suitable raw materials for the inventive 
process it is important that the mean fibre length of the cellulose is 
less than the desired mean diameter of the resulting porous particles. 
It will generally be no problem to find suitable raw materials among dry 
and preferably pure celluloses for a person skilled in the art. 
It is also an important condition in the process according to the present 
invention that the cellulose raw materal initially is substantially dry, 
having at least 70% solids, suitably at least 80% and preferably at least 
90% solids (see also patent specification U.S. Pat. No.4,464,224, column 
4, lines 10-35). Subsequently, the substantially dry cellulose raw 
material is wetted by a gradual supply of an aqueous-based liquid during 
the manufacturing to porous matrices. 
It is furthermore an important condition that the cellulose raw material is 
initially pure, when the process according to the invention is used to 
produce cellulose matrices for pharmaceutical use. Celluloses fulfilling 
this criteria are those that are sufficiently pure, optionally after 
washing with a washing agent, so that the cellulose matrices produced 
according to the present invention meet the standard for powdered 
cellulose set by e.g. the British Pharmacopoeia 1993, p. 120. Thus, in the 
present invention the content of ether-soluble substances should be below 
0.15% (w/w) and/or the content of water-soluble substances should be below 
1.0% (w/w). 
Prior to optional loading of bioactive substances, the porous cellulose 
matrices used to prepare the multiple unit preparations and tablets 
according to the present invention, suitably contain less than 0.15% (w/w) 
of ether-soluble substances and less than 1.0% (w/w) of water-soluble 
substances according to the test method for powdered cellulose in British 
Pharmacopoeia 1993, vol. 1, Effective date: 1 Dec. 1993, London: HMSO, p. 
120. 
The mainly spherical porous cellulose matrices manufactured according to 
the process of the present invention have a reproducible porosity, 
particle size i.e. largest diameter, and size distribution in the particle 
range of about 0.1 to 3 mm, preferably between 0.3 and 2 mm, and have a 
tap bulk density lower than 0.8 g/ml, preferably less than 0.7 g/ml. 
These cellulose matrices are especially useful in the manufacture of 
multiple unit preparations (MU preparations) containing bioactive 
substances, which are incorporated in the matrices in a second step. 
The release of the bioactive substances from the matrices can be controlled 
by adjusting the porosity (the porous diffusion retarding network inside 
the matrices) during the manufacturing process, by selecting suitable 
cellulose fibres, by including release modifying substances into the 
matrices or by applying a barrier coating (release modifying membrane). It 
is possible to use soluble additives, such as sodium chloride in solid 
form included together with the cellulose before the mechanical treatment 
and thereafter dissolved from the matrices in order to further increase 
the porosity. In certain applications water insoluble substances can be 
added as porosity increasing additives which thereafter are dissolved in 
an organic solvent, see e.g. the Japanese Patent Specification 1272643. 
One or several bioactive substances and/or agents for modifying the 
stability, release rate or bioavailability of the bioactive substances can 
be applied, in any mixture or sequence, to the porous structure of the 
cellulose matrices in a solid, liquid, semi-liquid or gaseous form. The 
applied bioactive substances and/or agents are preferably a solid, a 
solution, a suspension, an emulsion, an oil, a super-critical fluid, a gas 
or a melt which can be sorbed, precipitated or sublimized into the porous 
structure in one or several steps, optionally with intermediate drying. If 
the one or several bioactive substances and/or agents are in solid, 
preferably in a powdery form, a mechanical mixing step will be necessary 
for applying the substance or substances to the matrices surfaces and 
optionally into the porous network of the matrices. Such a process can 
lead to a variety of preparations where adsorbing forces are used for a 
controlled loading and/or release of substances from a matrice according 
to the invention. 
The solid, liquid, semi-liquid or gaseous substance applied to the porous 
matrices can contain one or several agents or materials in order to modify 
the release rate of the bioactive substance. The materials for modifying 
the release rate are preferably selected from the group consisting of 
cellulose derivatives, acrylic acid derivatives, phospholipids, 
hydrocarbons, carboxylic acids, ethers, esters, alcohols, waxes and 
lipids, and mixtures thereof. The release rate can also be modified by 
agents such as surface-active substances to improve the dissolution rate 
of sparingly soluble substances and promote solubilization. 
The release rate of the bioactive substance or bioactive substances can be 
modified by applying a release controlling coating on the surface of the 
spherical particles. If used, the coating is selected from the group 
consisting of cellulose derivatives such as ethyl cellulose, acrylic acid 
derivatives and copolymers thereof, hydrocarbons, carboxylic acids, 
esters, ethers, alcohols, waxes and lipids, and mixtures thereof. 
The cellulose matrices can also be used as tabletting additives with or 
without incorporation of bioactive substances, especially in the form of 
compressed tablets and in direct compression, to obtain tablets that will 
disintegrate into discrete particles in water. 
Tablets could be prepared by admixing the matrices prior to compaction with 
bioactive substances and/or granules containing bioactive substances, in 
order to improve the tabletting process and/or tablet properties. Tablets 
could be prepared also by admixing the matrices, prior to compaction, with 
units containing bioactive substances of similar size, such as pellets, 
granules or crystals, which have been coated to modify the release 
properties of the bioactive substances, mask unpleasant taste or to 
improve the stability and thereafter compressing the mixture to tablets. 
When the porous cellulose matrices obtained by the process according to the 
invention is used for preparation of tablets the matrices loaded with 
bioactive substances can be directly compressed into tablets. 
When using the invention in the preparation of MU formulations, the basic 
concept is that the porous matrices of cellulose are formed in a separate 
process whereafter the pharmaceutical or pharmaceuticals (or other 
bioactive substances) are incorporated into the matrices in a second step. 
The size and size distribution of the final beads are determined in the 
first manufacturing step while amount of bioactive substance to be 
incorporated is controlled in the second step. The invention makes it 
possible to vary the amount of bioactive substance that can be 
incorporated but also to control the release rate of the bioactive 
substance as the cellulose network acts as a porous diffusion retarding 
system. The release properties may also be modified by adding suitable 
substances, such as polymers and waxes, during or after the incorporation 
of the bioactive substance or finally as a film coat. 
The invention is applicable in the production and use of various bioactive 
substances, such as pharmaceuticals, herbicides, insecticides, fertilizers 
and diagnostics whenever a controlled dosing and/or release is desirable. 
The bioactive substance is preferably a pharmaceutical compound. 
It is surprising that the simplified process according to the present 
invention leads to a result in the form of high quality porous cellulose 
particles with a high shape regularity and excellent loading properties. 
The process is especially advantageous compared to the previously 
disclosed process of WO 91/18590 by the possibility to use a wider variety 
of raw materials and by a more convenient treatment procedure with less 
preparation steps. It is also favourable in terms of its smaller and more 
convenient process equipment and because of the possibility to control the 
degree of shrinkage and swelling of the matrices. 
The following examples are intended to illustrate the invention without 
limiting the scope of protection as comprehended from the appended claims.

EXAMPLE 1 
200 g powdered cellulose (SOLKA-FLOC.TM. BW20, Mendell, USA) was charged 
into a low-friction high shear mixer with atomizer (Pellmix 1/8, Niro A/S, 
Denmark). 300 g water was added (18 ml/minute) via the atomizer. The 
impeller speed during the process was 600 revolutions per minute (RPM). 
Cellulose stucked on the wall and lid of the mixer was removed and combined 
with the bulk after 7 minutes. 
The lid was opened after adding the water, and the impeller was running at 
600 RPM for 10 minutes. The product-temperature was +37.degree. C. 
The moist porous cellulose matrices were dried on a tray in an oven 
(+60.degree. C., 24 hours). 
Yield (0.315-1.6 mm): 182 g (91%) 
Tap bulk density (0.71-1.00 mm, 1000 taps): 0.4 g/ml 
EXAMPLE 2 
203 g powdered cellulose (SOLKA-FLOC.TM. BW20, Mendell, USA) was mixed with 
20 g water in a planetary mixer (Kenwood Major) for 2 minutes and 
thereafter charged into a low adhesion high shear mixer with atomizer 
(Pellmix 1/8, Niro A/S, Denmark). 284 g water was added (18 ml/minute) via 
the atomizer. The impeller speed during the process was 600 revolutions 
per minute (RPM). 
Cellulose which stuck on the wall and lid of the mixer was removed and 
combined with the bulk after 8 minutes. 
The lid was opened after adding the water, and the impeller was running at 
600 RPM for 10 minutes. 
The moist porous cellulose matrices were dried on a tray in an oven 
(+60.degree. C., 24 hours). 
Yield (0.31-51.6 mm): 139 g (71%) 
EXAMPLE 3 
204 g powdered cellulose (SOLKA-FLOC.TM., Mendell, USA) was charged into a 
low adhesion high shear mixer with atomizer (1/8, Niro A/S, Denmark). 275 
g water and 27 g ethanol (95%) was added (18 ml/minute) via the atomizer. 
The impeller speed during the process was 600 revolutions per minute 
(RPM). 
Cellulose stucked on the wall and lid of the mixer was removed and combined 
with the bulk after 9 minutes. 
The lid was opened after adding the water/ethanol mixture, and the impeller 
was running at 600 RPM for 10 minutes. The product temperature was 
+37.degree. C. 
The moist porous cellulose matrices were dried on a tray in an oven 
(+60.degree. C., 24 hours). 
Yield (0.315-1.6 mm): 137 g (70%) 
EXAMPLE 4 
Tap bulk density for porous cellulose matrices (PCM) 0.71-1.00 mm 1000 taps 
for different cellulose qualities. 
______________________________________ 
Quality g/ml 
______________________________________ 
Elcema P050 
0.42 
Sanacel 90 
0.40 
Solka Floc BW20 
0.42 
______________________________________ 
Tap bulk density raw material 500 taps. 
______________________________________ 
Quality g/ml 
______________________________________ 
Elcema P050 
0.45 
Sanacel 90 
0.29 
Solka Floc BW20 
0.26 
______________________________________ 
This experiment shows that by processing the cellulose according to the 
invention the tap bulk density will be less than 0.7 g/ml. 
EXAMPLE 5 
Tabletting of porous cellulose matrices (PCM) prepared in accordance with 
the invention. 
The tablets were compressed at 100 MPa using 11.3 mm flat circular punches. 
PCM from the 0.71-1.00 mm fractions were used. 
Mean values from 5 tablets. 
______________________________________ 
Raw material 
Height (cm) 
Strength (N) 
Weight (mg) 
______________________________________ 
Solka-Floc BW20 
0.45 31 503 
Sanacel 90 0.43 105 500 
Elcema P050 
0.45 48 502 
Sanacel 300 
0.46 101 505 
______________________________________ 
As reference: 
______________________________________ 
Avicel PH101 
0.41 283 501 
Granulated in 
water/ethanol 
______________________________________ 
This experiment shows that matrices according to the present invention are 
possible to compress to tablets. 
EXAMPLE 6 
Loading the Matrices with Lidocaine 
1.04 g empty matrices 0.5-0.71mm according to Example 1 were charged into a 
100 ml glass vessel. 77 mg lidocaine were charged into a 25 ml glass 
beaker and dissolved in ethanol (95%). 
The solution was transferred to the vessel containing the matrices. The 
beaker was washed with ethanol. The ethanol was evaporated in a rotary 
evaporator (bath temperature approx. +45.degree. C.) for approx. 20 
minutes. Some deposits were found on the wall of the glass vessel. 
The loaded matrices were transferred to a glass bottle. The net weight was 
1.08g. 
Release of Lidocaine 
0.415 g of the loaded matrices were stirred in 360 ml 0.1M HCl at 
25.degree. C. with 150 revolutions per minute. 
Samples were taken after 5, 10, 15 and 60 minutes. They were analyzed 
spectrophotometrically at 230 nm. All samples contained approximately 59 
.mu.g lidocaine per ml. This corresponds to 51.2 mg lidocaine per g loaded 
matrices. The experiment shows that matrices according to the present 
invention exhibit satisfying release properties of the loaded 
pharmaceutical. 
EXAMPLE 7 
Three different batches were made in a Pellmix 1/8 to investigate the pore 
volume in accordance with Examples 1 to 3. Two formulations with 
microcrystalline cellulose (Avicel 100 and 101 and binders were compared 
to a formulation with dry powdered cellulose (SolkaFloc BW) without 
binder. 
______________________________________ 
Batch A: 
Avicel 100 
200 g 
Lactose 200 g 
HPMC E5 10 g 
Water 270 g 
Batch B: 
Avicel 101 
500 g 
Plasdone 10 g 
Water 750 g 
Batch C: 
SolkaFloc BW20 
203 g 
Water 304 g 
______________________________________ 
Mercury porosimetry was used to calculate the pore volume with the 
following results: 
______________________________________ 
Batch A 
0.275 cm.sup.3 /ml 
Batch B 
0.173 cm.sup.3 /ml 
Batch C 
0.888 cm.sup.3 /ml 
______________________________________ 
The experiment shows that a high level of porosity is obtained when a 
powdered dry cellulose is processed with the inventive method and that a 
higher porosity is obtained when using the dry pure untreated cellulose 
compared to conventional pellets of highly hydrolyzed microcrystalline 
celluloses and binders. 
EXAMPLE 8 
Porous cellulose matrices in the size range of 0.71-1 mm were prepared 
according to Example 2 above. To 10 g of the matrices 15 g of distilled 
water were added. The resultant mixture rested during 24 hours before 
freeze-drying by sublimation of water at -20.degree. C. It was found that 
the bulk density increased from 2.17 ml/g before freeze-drying to 2.48 
ml/g after freeze-drying. This is a measure of an increased porosity. 
The experiment shows that freeze-drying of the porous cellulose matrices as 
prepared according to the invention increases the porosity.