Note: Descriptions are shown in the official language in which they were submitted.
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The present invention relates to micro capsules having
semipermeable or permeable capsule walls and liquid cores and
to a process for producing same. By means of this process
sensitive materials can be encapsulated under physiological
conditions. The products thus obtained can be used for swooper-
lion and substance conversion-processes, in preparative and
analytical chemistry and biochemistry, in pharmacy and medicine
as well as in agriculture and in the food industry.
r~icrocapsules having semipermeable or permeable
capsule walls are known in the most varied forms ED Solodov-
nix: Mikrokapselung, Chimija, Moscow 1980; J. R. Nixon: Micro-
encapsulation Marcel Decker Inc., New York-Basel, 1976; J. E.
Vandegaer: Micro encapsulation Processes and Applications.
Plenum Press, Jew York-London 1974; M. Gulch: Capsule Tahitian-
logy and Micro encapsulation. Notes Data Corp., Park Ridge, 1972).
However, in many cases the polymers or polymer come
binations used for the capsule walls have disadvantages regard-
in -their permeation properties, their elasticity and motion-
teal stability, for example, at high osmotic pressure within
the capsule. The liquid core usually consists of an oily
organic liquid which is not miscible with water. This has a
disadvantageous effect on the properties of sensitive materials
to be encapsulated and on the passage of material - when using
micro capsules in aqueous systems.
Numerous mechanico-physical and chemical processes
for the production of microcàpsules are known. The principle
of the mechanico-physical encapsulation processes usually lies
in that the material for the core is sprayed and enveloped with
the wall material in a gas space. The wall material may
already be dissolved in the core material (spray drying) or sub-
sequently be brought into contact with the particles or droplets
of the core material as occurs in for example, immersion
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processes, multi component nozzle processes, and fluidized bed
processes.
Disadvantages of these processes lie primarily in
the application of elevated temperatures, the use of organic
solvents or the impermeability of the capsule sheath. The
chemical processes usually operate in liquid phase and the wall
is -formed by interracial polymerization or condensation or by
deposition of a specified wall material. The use of usually
reactive monomers and organic solvents usually constitutes
substantial disadvantages of the encapsulation processes by
interracial reactions.
Most of the chemical processes using a specified
polymer wall material have in common the fact that the core
material emulsifies or is suspended in the continuous phase
and that the polymer dissolved in the continuous phase precip
states at the phase boundary between core and continuum,
for example, by variation of the pi value, temperature and
additions of salts or solvents.
When encapsulating sensitive materials these condo-
lions easily result in damage to said materials.
In the case of the very frequently applied complex coalescence the wall material is precipitated by two oppositely
charged polymers (W. Slick: Anger. Chum. 87 (1975) page
556 to 567). The use of organic liquids, which are not Messiah-
bye with water, as the core material and the usually still
; necessary solidification of the capsule wall requiring some-
times very drastic reaction conditions are the most important
disadvantages of this process.
A relatively careful inclusion process comprises the
production of mixtures of the material to be encapsulated and
an aqueous polyelectrolyte solution and feeding this mixture
into a precipitating bath containing low-molecular ions. As a
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result of diffusion of ions structures having natural stability and a permeable gel network are formed (J. Klein, U. Hackle, P.
Sahara and P. Erg: Anger. Makromol. Chum. 76/77 (1977), page
329 to 350; German Auslegeschrift 19 17 733).
Because of the required pit variations nor the
presence of polyvalent metal ions this process also causes some
damage to sensitive materials. Furthermore, structures of this
kind have no permeable or semipermeable capsule wall and no
liquid nucleus.
process for immobilizing sensitive biological soys-
terms which is based on these gel particles and has been further
developed is described in the German Offenlegugnsschrift No.
3,012,233. In this process the bead-like particles are encom-
passed with a polyelectrolyte complex diaphragm by subsequent
treatment with a suitable polyelectrolyte solution and the
gel is reliquefied by ion exchange with corresponding buffer
solutions. The micro capsules thus obtained have the disadvan-
tare that they are very sensitive to external influences during
their production and when being handled since the capsule walls
have only a very low mechanical strength. The process does
not exclude the possibly harmful effect of polyvalent metal
ions.
Furthermore, the required reliquefaction of the gel
core by ion exchange constitutes an additional interference
with the entire system.
The present invention provides micro capsules having
improved properties and a process for producing same in order
to provide fresh possibilities for the micro encapsulation of
sensitive substances and to open up new fields of application
for the products thus obtained.
The present invention thus provides micro capsules and
a process for producing same, attempting and/or assuring at the
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same time the encapsulation owe sensitive materials. It is
possible to carry out the production of the capsules under con-
dictions as careful as possible, for example, under physiologic
eel conditions, and the capsule wall must be an elastic, per-
Mobil or semi-permeable diaphragm, which must be sufficiently
stable against chemical influences and mechanical s-tresses.
The inside of the capsule must be liquid and must not cause
any damage to the ma tori at to be encapsulated.
According to the present invention the process coy
proses passing the aqueous solution of a polyelectrolyte for
encapsulation in the form of reshaped preferably spherical
particles into the aqueous solution of an oppositely charged
polyelectrolyte or of an oppositely charged low-molecular or-
genie compound as a precipitating bath. The material -to be
encapsulated can be contained in the solution of the polyelec-
trolyte used as the core material. By mutual precipitation of
the oppositely charged polyelectrolyte components or of the
polyelectrolyte with the oppositely charged low-molecular or-
genie compound an insoluble diaphragm consisting of the cores-
pounding pol.yelectrolyte complex immediately forms on the sun-
: face of contact of the two solutions, said diaphragm enclosing
the material to be encapsulated, which is in the liquid core
material.
When using the process according to the present in-
mention said sheath constitutes a very thin but mechanically
stable diaphragm which is impermeable to dissolved high-
molecular compounds and encloses the polyelectrolyte solution
used as the core material and the substance to be encapsulated
when required. The nature of the polyelectroly-tes used or of
the low molecular organic ions, the precipitating conditions,
the concentration conditions in -the boundary layer and the
viscosity of the solution used as the core material determine
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the structure and properties of the diaphragm sheath formed.
It has been found that the thickness of the capsule wall in a
radial direction towards the inside of the capsule can be con-
trolled by varying residence times of the polyelectrolyte
solution droplets in the precipitating bath. With regard to
temperature and pi value of the polyelectrolyte solutions the
encapsulation conditions can be varied within wide limits.
however, for an encapsulation of sensitive materials as care-
fur as possible temperatures of 237 to 323 K and pi values off
5 to 9 are preferred.
Pure water can be used as a solvent for the polyp
electrolyte components concerned and for the low-molecular
organic ions.
In addition, the use of buffer mixtures, as for
example, 0.001 to 1 M phosphate buffer, or of solutions of
low-molecular electrolytes permits the controlled adjustment
of specific pi values and of varying ion strengths.
With regard to the polyelectrolytes to be used as
the core material in accordance with the present invention
polysaccharides or polysaccharide derivatives containing sulk
plate or carboxylate groups, as for example, cellulose sulk
plate, dextran sulfite, starch sulfite, carboxy-methyl eel-
lulls or allegiant, in the form of their sodium salts, alone
or in mixture have been found to be particularly suitable.
However, synthetic polymers containing carboxylate or
sulphonate groups, as for example, polyp or copoly-acrylates,
maleinates or polystyrene sulphonate are also suitable. The
polyelectrolyte concentration in the aqueous solution of the
core material can be varied between 0.5 and 20% by weight as a
function of the nature of the polyelectroltye used and of the
degree of polymerization
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kite the degree of substitution of the polysacchar-
ire sulfites and polysaccharide carboxylates can be varied
within wide limits, for example, between 0.3 and 2.5, the de-
grew of polymerization should not be too low since a certain
minimum viscosity is required for the stability of the micro-
capsules in the stage of mousiness. The viscosity of the finish-
Ed core material mixture should preferably be maintained within
the limits of 0.1 and 10 Pa-s and should be ten to a hundred
times that of the precipitating bath.
lo according to the present invention aqueous solutions
of polycations containing qua ternary ammonium groups, as for
example, polydimethyl-diallyl ammonium chloride and polyvinyl-
bouncily trim ethyl ammonium chloride, or of low-molecular organic
cations, particularly cation surfactants and/or cat ionic dyes
containing qua ternary nitrogen groupings are used for the
precipitating bath.
amongst the cation surfactants qua ternary ammonium
salts, as for example, lauryl-dimethyl-benzyl ammonium chloride,
pyridinium salts, as for example, stearamido-methylene pardon-
I'm chloride, and imidazolium salts, as for example, heptadecylimidazolium chloride, have been found to be suitable. The
hydrophylic long-chain alkyd or aralkyl radical of the surface
lent can be interrupted by hotter atoms or hotter atom groups,
for example, diisobutyl-phenoxy-ethyoxy-ethyl-dimethyl-benzyl
ammonium chloride, dodecyl carbamyl methyl bouncily dim ethyl
ammonium chloride.
For example, amino-triaryl-methane dyes, acridine
dyes, methane dyes, thiamine dyes, oXazinR dyes or ago dyes can
be used as cat ionic dyes. The concentration of polycation,
cation surfactant and/or cat ionic dye in the precipitating bath
should be 0.1 to 20% by weight, preferably 0.2 to 10% by weight.
The process according to the present invention is
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extremely simple to carry out. The aqueous polyelectrolyte
solution intended for the core material is first mixed with the
material to be encapsulated at the optimal pi value for the
Metro at to be encapsulated and at a suitable temperature.
The material to be encapsulated can already be present as an
aqueous solution, dispersion or in a solid form. The mixture
thus obtained is then mounded to spherical droplets by allowing
it to drip from a capillary tube or by blowing off the droplets
forming with elf or an inert gas for example, by using a con-
centric nozzle, and feeding them into the precipitating bath which is stirred or kept in motion in some other way and, when
required, is tempered and buffered. The capsule sheath forms
immediately upon mutual contact of core material droplets and
precipitating bath. For this reason the micro capsules can be
separated directly after being fed into the precipitating bath.
However, it is advantageous to leave the micro capsules in the
precipitating bath for another 10 seconds to 120 minutes or
longer. In this manner the thickness of the wall layer and its
properties are readily reproducible for identical material and
constant encapsulation conditions. In this case the wall
thickness is of the order of 0.1 to 50 em, but when low-molecu-
far ions of opposite charge are used it can be substantially
larger. The size of the micro capsules can be varied by a eon-
responding condition of the molding process and the viscosity
of the core-material solution can be varied within the limits
of 50 and 5,000 em. In order to attain homogeneous spherical
micro capsules, a gap of 5 to 200 cmj preferably 10 to 100 cm is
maintained between the discharge opening of the capillary tube
or of the nozzle and the surface of the precipitating bath.
The actual micro encapsulation is usually followed by
the separation of the micro capsules formed from the precipitate
in bath by filtering or decanting or rinsing the excess ad-
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honing precipitating bath with water or buffer solution.
For solidifying the capsule wall and reducing its
permeability the micro capsules can be treated with a diluted,
e.g., 0.01 to 1% aqueous solution of the polyelectrolyte used
as the core material. This treatment is suitably followed by
a further treatment in the precipitating bath.
The micro capsules produced according to the present
invention are very stable against deformation and increased
osmotic pressure. However, when subjected to intense mechanic
eel stress they burst and release the capsule content.
They can be frozen without damaging the capsule wall
upon thawing. They are also stable against chemical action,
as for example, 0.1 N Noah, 0.1N Hal, ethanol, acetone. For
low-molecular inorganic and organic substances, as for example,
protons, hydroxyl ions, water, dissolved salts and sugar the
diaphragm constitutes no substantial barrier to diffusion.
The process according to the present invention will
be explained in greater detail by means of the examples here-
after.
The present invention will be further illustrated,
by way of the following Examples.
Example 1
0.5 g of Na-cellulose sulfite having a degree of sub-
stitution of 2.0 is dissolved in 10 ml of 0.01N phosphate buff
for (pi 7.0). The solution thus obtained is forced at room
temperature through a capillary tube having an inside diameter
of 0.2 mm and after a height of drop of 30 cm it is fed drop-
wise into a stirred precipitating bath of 2 g of polydimethyl-
Delilah ammonium chloride (relative molecular weight 40,000)
30 and 100 ml of 0.01N phosphate buffer (pi 7.0). Immediately upon
entering the precipitating bath the drops become coated with a
film of the complex of the two oppositely charged polyelectro-
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lyres. After 30 minutes the micro capsules obtained are separate
Ed from the precipitating bath by decanting and washed with
0.01N phosphate buffer (pi 7.0). The spherical micro capsules
have a diameter of 2 to 3 mm and are transparent. They contain
the applied cellulose sulfite solution as the core material.
The capsule wall formed is free from defects and con-
statutes a diaphragm permeable to low-molecular substances.
On suspending the micro capsules in 0.01N Noah dyed with phenol
phthalein and decolonizing the dispersing medium with 0.lN Hal
after approximately three minutes the capsules still retain,
for several minutes, their red color, which then fades slowly.
When salt is added to the dispersing medium the particles
shrink at first while being deformed. When subsequently washed
with water they again assume their spherical shape.
Example 2
0.2 g of Na-cellulose sulfite having a degree of
substitution of 0.3 is dissolved in 10 ml of water. The soul-
lion thus obtained is forced through a capillary tube having
an inside diameter of 0~2 mm and so blown off via a concentric
nozzle with the aid of a stream of nitrogen that individual
liquid droplets having a diameter of 100 to 500 em are formed.
After a drop height of 15 cm the spherical droplets
enter a stirred precipitating bath of 2 g of polydimethyl-
dialkyl ammonium chloride and 100 ml of water. Immediately
upon contact with the precipitating bath the droplets become
coated with a film of the complex formed from the two opposite-
lye charged polyelectrolytes. After 30 minutes the microcopy-
sulks obtained are separated from the precipitating bath by
decanting and washed with water. Transparent spherical par
tides having a diameter of 100 to 500 em are obtained. Their
capsule wall thickness is 1 to 5 em.
SLY
Example 3
1.5 g of Na-dextran sulfite having a degree of sub-
stitution of 0.8 are dissolved in 10 ml of water. The solution
thus obtained is tempered to 277 K and, as in Example 1, it is
fed into a precipitating bath tempered to 277 K and consisting
of 10 g of polydimethyl-diallyl ammonium chloride and 100 ml
of water. After 60 minutes the micro capsules formed are spear-
axed from the precipitating bath by decanting, mixed with 100 ml
of a 0.1% dextrane~sulphate solution and then treated with the
precipitating bath for further 30 minutes. Micro capsules
having a diameter of 3 to 4 mm and a wall thickness of approx-
irately 20 em are obtained.
Example 4
0.3 g of Na-carboxy-methyl-cellulose sulfite having
a degree of substitution of carboxyl groups of 0.6 and of sulk
plate ester groups of 0.3 is dissolved in 10 ml of water. The
solution thus obtained is tempered to 313 K and, as in Example
1, fed into a precipitating bath tempered to 313 K and consist-
in of 3 g of polyvinyl-benzyl trim ethyl ammonium chloride and
100 ml of water. After 60 minutes the capsules are separated
from the precipitating bath by decanting and washed with water.
Transparent micro capsules having a diameter of approximately
3 mm are obtained.
Example 5
0.3 g of Na-cel]ulose-acetate sulfite is dissolved
in 100 ml of water. As in Example 1, the solution thus obtain-
Ed is fed drops into a precipitating bath obtained by disk
solving 3 g of polydimethyl-diallyl ammonium chloride in 100 ml
of dilute Hal having a pi value of 4. After 60 minutes the
capsules are separated from the precipitating bath by decanting
and washed with water. Transparent micro capsules having a
diameter of approximately 3 mm are obtained.
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Example 6
0.3 g of Na-polystyrene sulphonate is dissolved in
100 ml of water. As in Example 1, the solution thus obtained
is fed drops into a precipitating bath of 3 g of pulled-
methyl-diallyl ammonium chloride and 100 ml of water. After 30
minutes the capsules are separated from the precipitating bath
by decanting and washed with water. Whitish-turbid microcopy-
sulks having a diameter of approximately 2 mm and a liquid core
are obtained.
Example 7
.
0.2 g of Na-cellulose sulfite having a degree of
substitution of 0.4 is dissolved in 9.8 ml of water. At room
temperature the solution thus obtained is forced through a cap-
illary tube having an inside diameter of 0.2 mm and after a
drop height of 30 cm it is fed drops into a stirred precip-
stating bath of 1 g of ethylene blue and 99 ml of water.
Immediately upon entering the precipitating bath the capsules
become coated with a film. After 30 minutes the capsules form-
Ed are separated from the precipitating bath by decanting and
washed with water. Spherical capsules having a deep blue
color and a diameter of 3 to 5 mm are obtained.
example 8
0.3 g of Na-carboxy-methyl cellulose having a degree
of substitution of 0.6 is dissolved in 9.7 ml of water. the
solution thus obtained is forced through a capillary tube have
in an inside diameter of 0.2 mm and is so blown off via a
concentric nozzle with the aid of a nitrogen stream that India
visual liquid droplets having a diameter of 100 to 300 em are
formed. The droplets are blown into a stirred precipitating
bath of 2 g of dodecyl-carbamyl-methyl-benzyl-dimethyl ammonium
chloride and 98 ml of water. After 120 minutes the microcopy-
sulks formed are separated from the precipitating bath with the
1;~3~
aid of a fine polyamide sieve and thoroughly washed with water.
White, nontransparent spherical particles having a diameter of
100 to 300 em are obtained.
Example 9
0.2 g of Na-carboxy-methyl cellulose having a degree
of substitution of carboxyl groups ox 0.6 and of sulfite ester
groups of 0.3 is dissolved in 9.8 g of water. As in Example 7
the solution thus obtained is mounded to spherical droplets and
fed into a precipitating bath of 1 g of crystal violet (C. J.
Basic Violet 3) and 99 ml of water. After 10 minutes the cap-
sulks formed are separated from the precipitating bath by de-
canting and thoroughly washed with water until the water no-
mains colorless. The capsules have a dark violet color and a
diameter of 3 to 5 mm.
Example 10
0.2 g of Na-cellulose sulfite having a degree of
substitution of 0.4 is dissolved in 9.8 ml of water. The soul-
lion obtained is molded to spherical particles as in Example 8
and fed into a precipitating bath of 2 g of safranine (C. J.
Basic Red 2) and 98 ml of water. After 30 minutes the micro-
capsules are sieved from the precipitating bath and thoroughly
washed with water. Dark red spherical particles having a
diameter of 100 to 300 em are obtained.
Example 11
0.2 g of Na-alginate is dissolved in 9.8 ml of water
and the solution is molded to spherical particles as in Example
7. Said particles are fed into a stirred precipitating bath
of 1 g of safranine (C. J. Basic Red 2), 1 g of polydimethyl-
Delilah ammonium chloride and 98 ml of water. After 60 minutes
the capsules are sieved and washed with water. Dark red sphere
teal particles having a diameter of 3 to 5 mm are obtained.
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Example 12
0.2 g of Na-cellulose sulfite having a degree of
substitution of 0.4 is dissolved in 9.8 ml of water. As in
Example 7 the solution thus obtained is forced through a cap-
Lowry tube and fed drops into a precipitating bath of 1 g of
acridine orange (C. J. Basic Orange 14) and 99 ml of water.
After 60 minutes the capsules are sieved and washed with water
until the draining wash water is colorless. Spherical particles
having an intense orange color and a diameter of 3 to 5 mm
are obtained.
Example 13
0.2 g of Na-polystyrene sulphonate is dissolved in
9.8 ml of water. The solution thus obtained is forced through
a capillary tube as in Example 7 and fed drops into a pro-
cipitating bath of 2 g of benzethonium chloride and 98 ml of
; water. After 2 hours the capsules formed are sieved and
thoroughly washed in water. White, nontransparent spherical
particles having a diameter of 3 to 5 mm are obtained.
Example 14
0.2 g of Na-cellulose sulfite is dissolved in 9.8 ml
of water and the solution thus obtained is forced through a
capillary tube as in Example 7, whereupon it is fed drops
into a precipitating bath of 2 g of lauryl-dimethyl-benzyl
ammonium chloride and 98 ml of water. After two hours the
capsules thus formed are sieved and thoroughly washed with
water. White, nontransparent spherical particles having a
diameter of 3 to 5 mm are obtained.
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