U.S. patent application number 10/851702 was filed with the patent office on 2004-11-04 for method to obtain microparticles.
Invention is credited to Sjoblom, Brita.
Application Number | 20040219222 10/851702 |
Document ID | / |
Family ID | 20416948 |
Filed Date | 2004-11-04 |
United States Patent
Application |
20040219222 |
Kind Code |
A1 |
Sjoblom, Brita |
November 4, 2004 |
Method to obtain microparticles
Abstract
A method for the preparation of homogeneous microparticles
containing a pharmaceutically active substance by a spray freezing
technique wherein the medium to be atomized into droplets has a
high dry content and comprises besides the active substance a
polymer and a liquid (in which the polymer may be soluble) in which
the active substance and polymer are suspended, dissolved or
emulsified.
Inventors: |
Sjoblom, Brita; (Hovas,
SE) |
Correspondence
Address: |
WHITE & CASE LLP
PATENT DEPARTMENT
1155 AVENUE OF THE AMERICAS
NEW YORK
NY
10036
US
|
Family ID: |
20416948 |
Appl. No.: |
10/851702 |
Filed: |
May 20, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10851702 |
May 20, 2004 |
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09674043 |
Oct 23, 2000 |
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6753014 |
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09674043 |
Oct 23, 2000 |
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PCT/SE00/01682 |
Sep 1, 2000 |
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Current U.S.
Class: |
424/489 ;
264/5 |
Current CPC
Class: |
A61K 9/1694
20130101 |
Class at
Publication: |
424/489 ;
264/005 |
International
Class: |
A61K 009/14; A61K
009/16; A61K 009/50 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 10, 1999 |
SE |
9903236-9 |
Claims
1. A method of preparing homogeneous microparticles containing a
pharmaceutically active substance by use of a spray freezing
technique which method comprices atomizing into droplets a liquid
medium having a minimum dry content of 15% by volume and comprising
a) a pharmaceutically active substance, b) a polymer selected from
the group consisting of water soluble polymers and non-water
soluble polymers, said polymer being present in an amount of at
least 5 per cent by weight based upon the dry content of the
medium, c) a liquid in which the pharmaceutically active substance
and polymer are suspended, dissolved or emulsified, and d)
optionally a dispersing agent, selected from the group consisting
of polymers, surfactants, other substances and mixtures thereof,
freezing the formed droplets and sublimating the frozen liquid of
the droplets to obtain dry, homogeneous microparticles.
2. A method according to claim 1, wherein the polymer of the liquid
medium constitutes 10 weight % or more of the dry content.
3. A method according to claim 1, wherein the polymer of the liquid
medium constitutes 15 weight % or more of the dry content.
4. A method according to claim 1 wherein the dry content of the
liquid medium is from 15 to 60 vol %.
5. A method according to claim 1, wherein the dry volume content of
the liquid medium is from 15 to 60 vol % and gives dry
microparticles with a relative density of 15 to 60 %.
6. A method according to claim 1, wherein the dry volume content of
the liquid medium is from 15 to 60 vol % and gives dry
microparticles with a porosity of 85 down to 40 vol %.
7. A method according to claim 1 wherein the liquid medium to be
spray-freezed is a suspension.
8. A method according to claim 1 wherein the liquid medium to be
spray-freezed is a solution.
9. A method according to claim 1 wherein the liquid medium to be
spray-freezed is an emulsion.
10. A method according to any of the preceding claims wherein the
content of the pharmaceutically active substance is from 60 to 95
weight %, preferably 75 to 90 weight %, of the weight of the dried
microparticles.
11. A method according to any of the preceding claims wherein the
dry content of the medium is from 15 to 60 vol % and with the
content of the pharmaceutically active substance being from 60 to
95 weight % of the dried microparticles.
12. A method according to any of the preceding claims wherein the
polymer is selected from the group consisting of a cellulose
derivative, a polysaccharide, a natural polymer, a synthetic
polymer, a surfactant and mixtures thereof.
13. A method according to any of the preceding claims wherein the
dispersing agent is selected from the group consisting of polymers,
surfactants, other substances and mixtures thereof.
14. A method according to any of the preceding claims wherein the
liquid in which the polymer is soluble is selected from the group
consisting of water, tertiary butyl alcohol, cyclohexane, methylene
chloride, methanol, ethanol and mixtures thereof.
15. A method according to any of the preceding claims wherein the
cold medium is selected from the group consisting of liquid
nitrogen, liquid argon, liquid oxygen or a cooled solvent well
below the freezing point of the liquid in the suspension.
16. A method according to any of the preceding claims wherein the
sublimation is performed by freeze-drying.
17. A method according to any of the preceding claims wherein the
size distribution of the prepared microparticles are in the range
from 10 to 1000 .mu.m.
18. Microparticles when prepared according to the method of any of
claims 1-17.
19. The microparticles according to claim 18 further comprising a
polymeric film coating.
20. A method of preparing homogenous microparticles containing a
pharmaceutically active substance, the particles being coated with
a polymer film coating, which method comprises a method as claimed
in any one of claims 1-17 followed by coating the microparticles
with a polymeric film coating.
Description
FIELD OF INVENTION
[0001] The present invention provides a method of obtaining
microparticles by a spray freezing technique. More specifically the
present invention relates to a method by which spherical
microparticles containing one or more pharmaceutically active
substances can be prepared.
BACKGROUND OF THE INVENTION
[0002] The strategy for pharmaceutical formulation of a given drug
depends on different factors. Ultimately, these factors emanate
from 1) the therapeutic needs, 2) the physical chemical properties
of the drug, and 3) the influence of the biological environment
where the formulation will release its contents. Thus, both
technical and biopharmaceutical considerations will contribute to a
successful therapy.
[0003] However, improved drug administration may also be achieved
by so called modified release of the drug, which has been discussed
extensively in the literature, e g R L Langer and D L Wise (Eds)
"Medical Applications of Controlled Release", vols I, II (1984),
CRC Press Inc, Boca Raton.
[0004] Several approaches to achieve different types of modified
release are described in the references above. Of special
importance to the present invention is modified release achieved by
formulating the active substance with a suitable carrier material
in the form of microparticles. Such a formulation then contains
multiparticulate discrete delivery units, each of which can be
coated if necessary with, e g a suitable pH sensitive,
semipermeable or other polymeric film. Several advantages can be
obtained with this type of formulation compared with more
conventional delivery means. Thus, the small size of the
microparticles assures a fast and predictable emptying from the
stomach, which is of special importance in the presence of food.
Further, the particles will spread over a larger area in the whole
GI-tract compared with a conventional monolithic (single-unit)
formulation. This will result in a safer therapy when the active
substance has local irritating side effects. Controllable plasma
levels of absorbed drug can also be obtained. The microparticle
formulation will also have a longer residence time in the colon
which makes 24 hrs extended release formulations possible. From a
technological point of view, microparticles are more suitable for
coating and handling since a technical fault during the process may
be serious for single unit formulations but less so for
micropellets. Also, microparticle formulations are more easily
manufactured and prepared in different doses than standard tablet
systems.
PRIOR ART
[0005] An ideal method for the preparation of microparticles where
the drug is homogeneously distributed within a polymeric matrix,
should be simple, reproducible, rapid and minimally dependent on
the solubility characteristics of the drug. A high product yield
and a high degree of retention of the active substance in the final
microparticles should also be obtained.
[0006] Several different techniques are available for making
microparticles (<1 mm), e g spray-drying,
extrusion-spheronization, spray-chilling, emulsion solvent
evaporation/extraction and coating of nonpareil spheres, among
others. A recent review was presented by Conti et al in STP Pharma
Sci 7, 331 (1997) where the technical aspects of coacervation,
spray-drying, emulsion solvent extraction, and emulsion solvent
evaporation were discussed.
[0007] However, all existing techniques suffer from one or more
drawbacks. Thus, many drugs are sensitive to heat and therefore
will deteroriate which restricts the use of spray-drying or
spray-chilling.
[0008] In extrusion spheronization and in coating of non-pareils
particles it has been difficult to achieve acceptable
microparticles in the size range of 50-400 .mu.m. Pellets made by
these methods contain significant amounts of inert excipients. This
may make the pelletization of high-dose drugs by these methods a
difficult task.
[0009] Finally, in emulsification solvent evaporation, an emulsion
has to be made and the drug to be incorporated is preferably
lipophilic, which restricts the drugs which can be used. Another
drawback is the toxicity of the solvent used, usually methylene
chloride, which can remain in the microparticles after drying.
[0010] However, despite the many different approaches there has not
been disclosed a technique that can produce both smaller
microparticles but also particles of more uniform size. It is
important to avoid, e g segregation and dose variation during
further processing into capsules or tablets. Further, the existing
techniques do not incorporate several desirable aspects such as the
possibility to produce spherical microparticles of different size
ranges that are homogeneous, have a high drug content and
sufficient mechanical strength (to e g withstand coating processes)
into one single technique.
[0011] A spray-freezing technique has been used for the processing
and granulation of ceramic materials to achieve homogeneous
distribution of additives within granules to be compacted. For the
processing of slurries containing silicon-nitride, sintering
additives and a binder, spherical free-flowing granules have been
prepared by spray-freezing and subsequent freeze-drying. The
homogenity of the slurry was retained in the granules and thus in
the final sintered product (Nyberg et al, Euro-Ceramics II 1, 447
(1993)). Suspensions of silicon carbide and additives were
processed in this way to give granules for compaction (U.S. Pat.
No. 4,526,734). The increased homogenity compared with traditional
granulation techniques resulted in better mechanical properties of
a whisker reinforced ceramic (EP 0 584 05 1). The process is also
feasible. for making homogeneous powder blends for ceramic
superconductors (Japanese unexamined patent application no.
59-102433).
[0012] Normally pharmaceutical materials are lyophilized by
freeze-drying in a bulk process in which the solution/suspension to
be freezed is placed in vials or on trays in a freeze-drier, where
freezing and subsequent sublimation of the dry solvent take place.
The dried product is a powder cake.
[0013] The rapid freezing provided by spray-freezing ensures that
no concentration gradients exist in the resulting frozen particles
and degradation of biological material is prevented. This approach
has been used to achieve precise metering and dispensing (M J Akers
and D J Schmidt, BioPharm 28, (April 1997)); where the frozen
particles were in the form of large lumps of size 1-9 mm. Freezing
of droplets in a moving bath of Freon 12 (-20.degree. C.), which
medium conflicts with environmental demands, has been used to
obtain porous, free-flowing, spherical granules with rapid
dissolution (U.S. Pat. No. 3,932,943); as well as making homogenous
granules for tableting with precise dosing (U.S. Pat. No.
3,721,725).
[0014] A process for preparing foamed bioabsorbable polymer
particles for surgical use was presented in U.S. Pat. No.
5,102,983. Here, however, the porosity was very large, and the pore
sizes in the range of 4-10 .mu.m, the dry content of the solution
being sprayed being 1-20 wt %.
[0015] U.S. Pat. No. 5,019,400, disclosed the use of a mixture of a
biologically active material, a polymer, and a solvent which was
sprayed into a non-solvent cooling medium that freezed the droplets
with subsequent extraction of the solvent in the droplets during
heating. The particles were finally dried in a vacuum-drier. The
microparticles formed were porous, and contained 0.01-50 % of the
active substance. The dry content of the solution sprayed was 6wt
%. This process is not entirely satisfactory since it is an
advantage to have one single drying step after freezing and also a
higher active substance content than 50 wt % in order to make high
dose materials.
[0016] U.S. Pat. No. 5,405,616 discloses a method of forming
droplets by forcing a suspension/solution/emulsion through
calibrated jets. The droplets then fall into liquid nitrogen. Due
to low shear forces the size of the pellets formed is large; 0.2-12
mm, which would then give a less safe dosability than if smaller
particles could have been achieved. The smallest particles achieved
were 0.8-1 mm. Further, to achieve low friability pellets, the
drying step after freeze-drying was performed by thawing the
pellets before conventional vacuum drying. To achieve these low
friability pellets the matrix former is restricted to materials
that during thawing will form a gel. The particles obtained contain
no more than 33 wt % of the active substance.
[0017] To the skilled person particle production utilizing the
technique described in U.S. Pat. No. 5,405,616 appears to be quite
a slow process and not suitable for large scale industrial
pharmaceutical production.
OBJECT OF THE INVENTION
[0018] An object of the present invention is to provide a method
for the production of microparticles. More specifically, the method
is for the production of homogeneous microparticles which does not
have the drawbacks of the methods discussed above, e.g. methods
that rely on heat or multiple solvents for drug dissolution, but
instead puts no restrictions on the drug to be incorporated. A
further object is to provide a method for the production of
microparticles with controllable amounts of incorporated drug in a
high-yield process. Also, the invention provides a method to
produce homogeneous microparticles with an incorporated drug that
have low friability so that they for instance can withstand coating
processes. A further object of the invention is to provide a method
to produce microparticles that have easily controllable density and
strength. A further object is to obtain microparticles with a high
content of active substance.
DISCLOSURE OF THE INVENTION
[0019] It has now been found that free-flowing, homogeneous
microparticles having low friability can be obtained by
spray-freezing a suspension, solution or emulsion of a
pharmaceutically active substance with subsequent freeze-drying of
the frozen microparticles. The microparticles are preferably
spherical in shape. The porosity of the microparticles obtained is
controlled in the process by the dry content of the suspension,
solution or emulsion. Apart from the porosity, the brittleness of
the microparticles is controlled by the amount of polymer binder
included in the suspension, solution or emulsion. In order to
obtain low friability particles the dry content of the suspension
or solution or emulsion should be high.
[0020] Generally the following conditions are applicable to obtain
low friability microparticles according to the method of the
invention;
[0021] Low friability microparticles that can for instance
withstand coating with a polymeric film, are achieved when the
suspension, solution or emulsion has a dry volume content of at
least 15 vol %, preferably up to 60 vol %, and a polymer binder
content of at least 5 weight %, preferably 10 weight % or more, and
more preferably 15 weight % or more (based upon dry content). A
high total pharmaceutically active substance content can be
obtained by using the present invention, such as up to 95 weight %
or preferably 90 weight % (based upon dry content). The median pore
size of the microparticles obtained being preferably a maximum of
1.0 .mu.m. Dry content and dry volume content are weight % and
volume %, respectively, of dry material in the
suspension/solution/emulsion (dry/(dry+liquid)), wherein the dry
material is pharmaceutically active substance+polymer.
[0022] According to the present invention homogenous low friability
microparticles can be obtained when the dry content is from 15 to
60 vol % and the polymer binder content is 5 weight % or more
giving dry microparticles with a relative density of 15 to 60 % (a
porosity of 85 down to 40 vol %). [Relative density: weight of
freeze-dried material/volume of freeze-dried material/theoretical
density of dry material].
[0023] The content of the pharmaceutically active substance
calculated on the weight of the dried microparticles may be from 60
to 95 weight %, preferably from 75 to 90 weight %.
[0024] The dry content of the liquid medium is defined as the
residue after drying at 110.degree. C. for 2 hours, divided by the
total amount before drying. The dry content can be expressed either
as weight percent or, preferably, as volume percent.
[0025] The success in obtaining low porous microparticles and thus
low friable microparticles depends on the volume fraction of dry
material and the amount of polymer binder. The dry content of a
suspension/solution/emulsion should thus preferably be expressed as
a volume fraction although this cannot always be calculated.
[0026] The microparticles may be obtained by spraying a homogeneous
suspension, solution or emulsion of the active subtance(s) through
an atomizer into a vessel with a cold medium with a temperature
well below that of the freezing point of the liquid in the
droplets. Frozen droplets will then form instantaneously. The
structure of the suspension, solution or emulsion is retained in
the droplets providing a homogeneous distribution of the substances
within the droplets. The frozen liquid is then sublimated by
freeze-drying of the frozen droplets where the structure of the
droplets is retained due to lack of migration of substances during
drying.
[0027] The following general steps of the procedure are further
exemplified in the Experimental Section below:
[0028] a) Preparation of a medium for atomizing. The medium is a
suspension, a solution or an emulsion of the active substance. A
suspension may be prepared by dissolving or dispersing a polymer in
a liquid (as defined below), and then adding fine particles of the
active substance. A further dispersing agent (typically in an
amount of less than 20% (w/w) of the polymer amount) might also be
included to facilitate the dispersion of the active substance. The
polymer might then act as a binder between the fine active
substance particles in the microparticles and can be either a water
soluble or a non-water soluble polymer, according to definitions
below.
[0029] b) Atomizing of the suspension/solution/emulsion into
droplets. The suspension, solution or emulsion is fed by e.g. a
peristaltic pump through a nozzle that could be a pneumatic nozzle,
an ultrasonic nozzle, a rotary atomizer or a pressurized nozzle. A
typical size distribution of spheres produced by this process can
range from 1000 .mu.m down to 10 .mu.m.
[0030] c) Freezing of the formed droplets: The atomizer is situated
above the cold medium in a cylindrical vessel. If the cold medium
is a liquified gas the droplets in the spray formed by the nozzle
hit the cold boiling gas before hitting the cold medium that is
stirred to get a better wetting of the droplets. Instant freezing
takes place and the structure of the homogeneous suspension is
retained within the frozen microparticles.
[0031] d) Sublimation of the frozen liquid within the droplets: The
frozen droplets are transferred from the cold medium to a
freeze-drier to sublimate the frozen liquid. This step takes place
without any shrinkage of the droplets or migration of excipients (
e g polymers) and thus the structure of the
suspension/solution/emulsion is retained within the dry
microparticles.
[0032] The polymer or dispersing agent used for the formulation may
be a dry polymer that is partly or fully soluble in the liquid. The
polymer or dispersing agent used might also be a dispersion of
polymer particles (e g a latex).
[0033] The polymer or dispersing agent could be but are not limited
to the excipients listed below.
[0034] cellulose derivatives, like ethylcellulose, hydroxypropyl
methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
ethyl hydroxyethyl cellulose, carboxymethyl cellulose, cellulose
acetate butyrate, cellulose acetate phtalate, methylcellulose,
etc
[0035] other polysaccharides, like alginate; xanthan; carrageenan;
scleroglucan; pullulan; dextran; hyaluronic acid; chitin; chitosan;
starch; etc
[0036] other natural polymers, like proteins (e g albumin, gelatin,
etc); natural rubber; gum arabic; etc
[0037] synthetic polymers, like acrylates (e g polymethacrylate,
poly(hydroxy ethyl methacrylate), poly(methyl methacrylate),
poly(hydroxy ethyl methacrylate-co methyl methacrylate), Carbopolg
934, etc); polyamides (e g polyacrylamide, poly(methylene
bisacrylamide), etc); polyanhydrides (e g poly(bis
carboxyphenoxy)methane, etc); PEO-PPO block-co-polymers (e g
poloxamers, etc); polyvinyl chloride; polyvinyl pyrrolidone;
polyvinyl acetate; polyvinyl alcohol; polyethylene, polyethylene
glycols and co-polymers thereof; polyethylene oxides and
co-polymers thereof; polypropylene and co-polymers thereof;
polystyrene; polyesters (e.g. poly(lactic acid), poly(glycolic
acid), poly(caprolactone), etc, and co-polymers therof, and
poly(ortho esters), and co-polymers thereof; polycarbonate;
cellophane; silicones (e.g. poly (dimethylsiloxane), etc);
polyurethanes; synthetic rubbers (e.g. styrene butadiene rubber,
isopropene rubber, etc); etc
[0038] surfactants, e.g. anionic, like sulphated fatty alcohols (e
g sodium dodecyl sulphate), sulphated polyoxyethylated alcohols or
sulphated oils, etc; cationic, like quaternary ammonium and
pyridinium cationic surfactants, etc; non-ionic, like polysorbates
(e.g. Tween), sorbitan esters (e.g. Span), polyoxyethylated linear
fatty alcohols (e.g. Brij), polyoxyethylated castor oil (e g
Cremophor), polyoxyethylated stearic acid (e g Myrj), etc.
[0039] other substances, like shellacs; waxes (e.g. carnauba wax,
beeswax, glycowax, castor wax, etc); nylon; stearates (e.g.
glycerol palmitostearate, glyceryl monostearate, glyceryl
tristearate, stearyl alcohol, etc); lipids (e g glycerides,
phospholipids, etc); paraffin; lignosulphonates; etc.
[0040] Also, combinations of these excipients are possible.
[0041] The excipients mentioned above can be toughened by
introducing a plasticizer. The plasticizer can be but is not
limited to the plasticizers mentioned below.
[0042] glycerin, polyethylene glycol, propylene glycol, triethyl
citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate,
sorbitol, triacetin, etc
[0043] Also, combinations of these plasticizers are possible.
[0044] The liquid used for the preparation of the
suspension/solution/emul- sion, can be a solvent for the excipients
listed above and encompass, e g water or organic solvents with
freezing points well above the freezing point of the medium used
for freezing as exemplified below. Liquids, alone or a mixture of,
suitable to make a suspension/solution/emulsion of the active
substance, can then be, but are not limited to:
[0045] water (melting point (mp) 0.degree. C.), tertiary butyl
alcohol (mp 25.5.degree. C.), cyclohexane (mp +6.degree. C.),
methylene chloride (mp -95.1.degree. C.), acetone (mp -95.3.degree.
C.), methanol (mp -94.degree. C.), ethanol (mp -117.degree. C.),
etc;
[0046] The cold medium can typically be a liquified gas, e.g.
liquid nitrogen (boiling point -196.degree. C.), liquid argon
(boiling point -186.degree. C.), liquid oxygen (boiling point
-183.degree. C.), or a cooled solvent well below the freezing point
of the liquid in the suspension.
[0047] The mechanical strength of the microparticles is important
for determining whether they will withstand processing with a
polymer coating in a fluid bed.
[0048] Examining the microparticles with a microscope before and
after the fluidization in a fluid bed will give an indication of
their mechanical strength.
[0049] To achieve a relative measurement of mechanical strength the
pressure where microparticles started to deform was evaluated.
Microparticles within a certain size range (sieve fraction) were
placed as a monolayer onto the surface of a probe with a certain
area. Different loads (forces) were applied to the layer of
microparticles for one minute.
[0050] Examination of the monolayer of microparticles before and
after loading was made in a Scanning Electron Microscope to see at
what load the microparticles started to deform. The pressure at
which the microparticles started to deform was then calculated.
[0051] Pharmaceutically active substances suitable to form
microparticles of this invention can be but are not limited to
peptides, proteins, low molecular organic substances, pro-drugs,
antigens, hormones.
[0052] Thus, a microparticle according to the present invention
comprises one (or several) pharmaceutically active substances with
one or several additional non-active substances, which are
dispersed within the microsphere.
[0053] Uncoated particles can be retrieved as they are easily
dissolved when they are immersed into a liquid due to their porous
structure.
[0054] The microparticles obtained can be coated with a polymer to
achieve either a time-controlled release, a site-controlled release
or a pH-dependent release. Suitable polymers for coating can be,
but are not limited to, the same type of polymers as listed
above.
[0055] The coated microparticles can be put into capsules or
incorporated into a tablet compressed by methods known by those
skilled in the art.
[0056] The formulations produced based on the microparticles,
coated or uncoated, can be given by different administration
routes, such as, but not limited to, the oral, the parenteral, the
nasal, the pulmonary, the rectal, the tonsillar, the buccal, the
intraocular, the vaginal etc, administration routes. The preferred
administrations are by the oral, nasal, pulmonary and rectal
routes.
[0057] Working Examples
[0058] The following examples illustrate different aspects of the
invention.
[0059] The size distribution of the obtained microparticles was
measured by sieving. By mercury porosimetry measurements the
bulk-density and pore-size distributions were determined. To
determine the median pore size the pressure range for mercury
intrusion corresponded to pore sizes between 0.0005 .mu.m and 10
.mu.m.
[0060] By subjecting a monolayer of the microparticles to
compaction forces their relative strength was measured.
EXAMPLE 1
[0061] Preparation of Microparticles with a High Loading of Dry
Content that Withstand Coating in a Fluidized Bed
[0062] A suspension containing talc powder was made according to
the composition below;
1 Talc powder (1-2 .mu.m) 90 g Talc powder (5-80 .mu.m) 210 g HPMC,
6 cps 80 g Tween 80 (polysorbate 80) 6 g Purified water 750 g
Weight percent of dry content in suspension: 34 (19.2 vol %)
[0063] First, polysorbate 80 was mixed with the water. The HPMC was
then added and dissolved during stirring with subsequent addition
of the substance. The suspension was then deagglomerated by
high-shear mixing. The deagglomerated suspension was fed through a
pneumatic nozzle with a diameter of 1.0 mm at a speed of about 15
ml/min. The pressure of the atomizer was 1 bar. The spray formed
first hit the cold gas above the liquid in a vessel filled with
liquid nitrogen that was stirred to get a better wetting and
instantaneous freezing of the droplets. The frozen droplets have a
higher density than liquid nitrogen which make them sink to the
bottom of the vessel. The frozen droplets/microparticles were then
placed in a conventional freeze-drier with a shelf-temperature of
-20.degree. C. The primary drying was performed stepwise at
-20.degree. C. to 0.degree. C. at 0.1 mbar. The dry microparticles
were free-flowing and spherical. Scanning Electron Microscopy
showed a homogeneous distribution of the talc powder with pores
(0.1-2 .mu.m) in between. The bulk density, median pore size and
mechanical strength was measured and the results are shown in table
2.
[0064] Compaction measurements showed that the microparticles
obtained had a low friability (high mechanical strength).
[0065] Fluidization of the microparticles in Example 1 in a
fluidized bed showed by microscopy that the microparticles did not
break down. These microparticles started to deform at a pressure of
94 kPa (sieve fraction: 450-630 .mu.m). Final coating with a
polymer in a fluidized bed proved that the microparticles could be
successfully coated.
EXAMPLE 2
[0066] Coating of Microparticles with a Polymeric Film
[0067] The microparticles from Example 1 were easily handled
without falling apart and tough enough to be successfully coated. A
fraction of 20 g of the microspheres, 150-300 .mu.m in size, were
successfully coated with an enteric polymer to a film thickness of
30 .mu.m, in a fluidized bed.
[0068] Characterization of Pellets Obtained in Example 1.
2TABLE 1 Size distribution. Sieving (weight fraction %) Fraction
Example 1 <100 .mu.m 1 100-150 .mu.m 2 150-300 .mu.m 22 300-450
.mu.m 32 450-630 .mu.m 26 630-800 .mu.m 12 800-1000 .mu.m 4
[0069]
3TABLE 2 Characterization of microparticles Mercury porosity Binder
measurements (wt %) Pore median based on size (.mu.m) Dry content
dry Bulk density (measured Mechanical strength Example no. (vol %)
content (g/cm.sup.3) range: 0.0005-10 .mu.m) Kpa Fraction 1 19.2 21
0.47 0.8 94 450-630 .mu.m
* * * * *