Note: Descriptions are shown in the official language in which they were submitted.
PT r, ~/9'2
PCT/CH 91 /00020
Encapsulation of Active Substances with Starch
The present invention relates to a method for encapsulating or
S coating one or more active compounds in a or with a carrier
substance, to an encapsulated or coated actiYe compound which is
coated by a carrier substance and to uses of the methods according to
the invention.
The presence of active compounds, such as, for example,
pharmaceuticals, adhesives, fragrances, detergent additives, dyes,
concrete additives, pesticides etc., in a reprocessible, reusable,
transportable, marketable etc. form has been a central problem for a
long time. In particular, active compounds must be protected from
15 environmental influences, such as moisture7 I JV radiation, mechanical
stress etc., and at the same time should be easy to meter and practical
to handle.
A large number of processes, methods and techniques is known
20 to present active compounds in a handleable form, as is necessary in
accordance with the abovementioned statement of the problem.
;
For example, the production of tablets, where essentially solid
active compounds are compressed into table~ form by a consolidating
2s means, is known. This form of handling is unsuitable, in particular, for
moisture- sensitive active compounds or for fine metering.
Paclcing in small bags, for example composed of plastic, has the
disadvantage that the packaging, i.e. the bag, must first be opened
3 o when using the active compounds, which, in particular with small
bags, is very impracticable. Moreover waste results if the bag is not
additionally usable.
Of particular interest is the coating or encapsulation of active
3 5 compounds, for which purpose in the latter case capsules or
microcapsules are prepared which are filled with the active
` :
,
- 2 ~ 3 ~
compound. The methods customary for the production of these
capsules or for their filling, however, are very complicated and
expensive, so that in particular with relatively inexpensive active
compounds they are hardly viable or not viable at all. The principle of
S this encapsulation has until now been essentially restricted to
pharmaceutical active compounds, as these active compounds are
relatively expensive and the costs of the encapsulation process are not
so crucial. This technique has previously been described in many
different ways, for which purpose, for example, reference is made to
10 the following specifications.
In EP-A-0,092,908, EP-PS-0,090,600, EP-A-0,118,240 and EP-A-
0,304,401 the production of capsules by injection moulding or deep
drawing is described, hydrophilic polymers, such as gelatin or starch,
5 being proposed for the production of the capsules, which can be
brought at least partially into thermoplastically processible form for
the processing and production of the capsules by means of suitable
processes. What is concerned here is exclusively the production of
capsules of the larger type, which are only filled with active
20 compounds or sealed after their production.
In the Encyclopedia of Polymer Science and Engineering, Vol. 9,
John Wiley & Sons, pp. 724 ff., various methods and applications and a
large number of literature citations about production methods for the
25 production of microcapsules are described. In these methods, an
active compound, such as, for example, an active agent, a core
material, a filler, a nuclide etc., is encapsulated by a carrier material, a
coating or a membrane etc. The size of these microcapsules is between
1 and 1000 ,um. The most important areas of application are in the
30 production of carbon-free copying papers and in the
microencapsulation of pharmaceutical active compounds.
In particular, the use of the rnethods used until now for
microencapsulation is described in detail in the Encyclopedia of
3~ Chemical Technology by Kirk-Othmer, 3rd Edition, Vol. 15, on pp. 487
ff. In this literature citation, reference may in particular be made to
the literature index on pp. 492 and 493.
3 2 ~ .3 ~
As the production of microcapsules per se has been described
adequately in the two literature citations mentioned and the various
production methods are varied and extensive, a detailed description
of the latter is dispensed with, the contents of these two literature
S citations herewith being considered all-embracing as a part of the
present introduction.
All the methods or techniques proposed above for producing
capsules or microcapsules have the important disadvantage that they
10 are very expensive and thus are only worth considering at all in
connection with expensive active compounds, such as, for example,
pharmaceutical products. This statement is further corroborated in
the literature citation of Kirk-Othmer on p. 491 in the last section in
that it is mentioned here that so-called "large scale" industrial use of
15 the production of microcapsules is limited as a result of high costs and
thus only has future prospects in the pharmaceutical area, medicine
and some special markets.
It is therefore an object of the present invention to develop a
20 method according to which active compounds and active substances
can be encapsulated or coated in a simple and inexpensive manner,
the carrier substance used for the encapsulation or coating preferably
including a material which can be additionally used in the reuse of the
active substance or the active compound, such that waste products are
2~ not formed nor is the further use of the active substance negatively
influenced by the carrier substance.
This object is achieved by a method, preferably according to at
least one of the claims, such as in particular according to one of Claims
30 1 or 18.
A method for encapsulating or for coating one or more active
compounds in a or with a carrier substance is proposed in which a
mixture of essentially native starch and at least one agent at least
35 partially swelling the starch is used as the encapsulating or coating
carrier substance and is mixed together with the active compound and
at least one emulsi~ler for encapsula~ion or for coating.
I~ is proposed in this case that the swelling agent includes at
least one substance such as is described in the characterising part of
one of Claims 2 to 5 or 9.
The agent which initiates swelling or which swells the starch is
preferably chosen in such a way that the active substance to be
encapsulated is poorly or sparingly soluble in the swelling agent.
Correspondingly, in the case of active substances highly soluble
10 in water, it is further proposed that on mixing the essentially native
starch with the agent swelling the starch moisture is at least partially
removed from the starch.
It may be preferable here that the at least partially swollen
15 starch contains less than 12% by weight of water during the
encapsulation or coating of the active compound, it being possible for
this to lead in a further preferred çmbodiment of the method
according to the invention to the rnost extensive freedom from water
of the swollen starch.
In addition, it is also possible that the active compound itself is
at least partially the agent swelling the starch or else is soluble in the
swelling agent.
2s Suitable swelling agents or agents which initiate the dissolution
of the starch which have in particular emerged are glycerol and
aminoalcohols, as are claimed in the characterising part of Claim 5. In
the case of the aminoalcohols, monomers and also oligomers of the
aminoalcohols mentioned can come into consideration here.
30 Triethanolamine, for example, has proved particularly suitable.
As is proposed according to the invention, an emulsifier is
additionally added to the mixture of native starch and the swelling
agent. Owing to the boundary surface activity, this emulsifier
35 concentrates on the surface of the swollen starch and influences the
wetting be~ween the active compound and the swollen starch. The
complete wetting of the swollen starch is assisted by the emulsifier, as
a result of which the absorption of the active substance by the starch
.
` .
- 5 - ~ `3.~
or the coating of the active substance is favoured. Preferably, it is
proposed that up to about 4% by weight, relative to the total mixture,
of the emulsifier be used.
. . .
In order further to ensure that the swelling agent/starch phase
does not form a coherent homogeneous material, it is further
proposed that on mixing the swollen starch with the active substance
at least one oily substance is additionally added, which is essentially
unable to form a homogeneous mixture with the starch, or in which
10 the oil and the swollen starch form two separate phases and the
swollen starch grains are coated with a film of oil or dispersed in the
oil.
Preferably, it is proposed that on mixing the swollen starch with
1S the active compound up to 10% by weight, preferably 5 to 10% by
weight, relative to the total mixture, of an oily substance is admixed,
` which does not allow hornogeneous mixing with the swollen starch. Itis essential here that the active compound, on the one hand, is not
soluble in this oily phase, and moreover it must be more wettable by
20 the swelling agent/starch phase than by the oil phase, as a result of
which it is ensured that the starch/swelling agent phase encloses the
active compound.
Likewise, in order to prevent the formation of a coherent
25 homogeneous material, it is further proposed that the native starch is
at least partially swollen and mixed with the swelling agent in such a
way that a grain structure is essentially retained. This means, for
example, that the temperature chosen is not so high that the grains
are melted and form a homogeneous amorphous starch phase. On the
30 other hand, the mechanical stress on the grains (shearing, kneading,
mixing) may only be so large that the active compound is
incorporated into the grains, but the grains are not destroyed. The
structural viscosity of the starch grains must not fall below a lower
limit which, for example, is about 20 Pa/sec at a shear rate of 100
35 sec~l. The swollen starch grairis in this case can already exhibit
` increased amorphous structure, but the individual grains still do not
coagulate, i.e. a homogeneous melt is still not formed. The so-called
particulate phase of the swollen starch must be retained.
t
. ` ` '
. ' ' ' :'
,
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- 6 - ~ s3
Thus, for example, the temperature must not be above 170C on
mixing the individual components when using 40% glycerol as the
swelling agent.
s
It is further proposed in the process according to the invention
that up to 60% by weight, preferably 30 to 50% by weight, of the
swelling agent is added. It is ensured by this that the formerly hard
native grains of the starch are adequately swollen up and thus form
o elastic grains into which the various active compounds can be easily
kneaded. The choice of the amount of added swelling agent added
here is strongly dependent on the swelling agent chosen, by which of
course active substances can also be effectively encapsulated with less
than 30% of added swelling agent, such as, for example, of water.
15 However, if more than 60% of a swelling agent is added, the grains
become too soft, so that they burst even under slight mechanical
stress and the granular, pulverulent material can agglutinate to give a
compact mass.
Depending on the required properties of the final product, and
also owing $o possible toxic properties of the swelling agent, it may
possibly be advantageous to at least partially remove the swelling
agent again after encapsulation or coating.
2~ In particular when using up to lO~o by weight addition of an oily
substance, the added amount of the ernulsifier used is preferably 1 to
2% by weight, relative to the total mixture.
The method according to the invention for encapsulating or for
30 coating one or more active compounds in a or with a carrier substance
in particular includes mixing a mixture of 2~ to 60% by weight of a
swelling agent to start to swell the native starch, preferably 30 to ~0%
by weight, 0.1 to 4% by weight of an emulsifier, 0 to 10% by weight of
an oily substance, and the remainder of native starch in a mixing
35 apparatus, such as a mixer, kneader or extruder, the mixing taking
place together with the active compound, preferably at elevated
temperature, in order to produce an essentially homogeneous
powder which contains the encapsulated or coated ac~ive compound.
.,
- ;
- 7 - ~ 3 0-,~ z~
The mechanical agitation in the mixer, kneader or extruder is carried
out at elevated temperature because the wetting and sorption process
of the swollen starch by the active substance takes place only very
slowly without these additional measures as a result of the high
5 viscosity of the starch/swelling agent phase. The swelling process can
also be carried out at roonn temperature, the following problems
emerging:
- Dependin~, on the content of swelling agent, it takes up to 24
hours for all the swelling agent to be absorbed.
o - Because of poor mixing, the homogeneity of the product is not
ensured (variously sized grains~.
In this case, the mixture is first heated to a temperature which
is below the melting temperature of the starch/swelling agent
15 mixture. The starch is then at least partially swollen by means of the
swelling agent, whereupon under the action of the mechanical
agitation the swollen starch coats the active compound or takes this
up by sorption, the emulsifier and possibly the oil causing an
essentially homogeneous powder to be formed instead of a coherent
20 material.
The following substances inter alia, for example, have proved
suitable as emulsifiers:
- lecithin,
25 - a polyoxyethylene derivative of a sorbitan ester, such as, for
example, Tween ~rom the company ICI,
- an ethylene oxide derivative of a sugar or sugar ester, sugar
alcohol and/or sugar alcohol ester.
A triglyceride can be used, for example, as the oily substance.
The metering of the carrier substance with the active
compound(s) is carried out by the choice of the mean particle size of
the native starch used and/or the degree of swelling of the starch or
35 the ratio of starch content to swelling agent. If, for example, the
starting material used is a native starch grain from maize whose mean
;~ particle size is in the range of about 14 llm, a starch grain of this type
can be essentially more poorly "filled" with an active substance than,
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- 8 - ~ ~eJ c 7 ~
for example, a native starch grain of the potato, whose mean particle
size is in the range of about 35 llm. As a generalisation, it can be said
that the larger the mean particle size of the native starch which is
used as a starting material, the more active compound can be coated
S with the same protective action. However, it has to be considered here
that larger grains probably have greater protective action, but the
total mixture of the encapsulated active substances is less
homogeneous.
o As the active substances once encapsulated cannot be ground, it
is therefore also important to control the particle size of the finally
encapsulated active compound via the particle size of the native
starch which is used as a starting material.
By means of the process according to the invention described
above, an encapsulated or coated active compound is prepared which
is covered by a carrier substance, the carTier substance for the
encapsulation or coating being essentially composed of at least
partially swollen starch.
The encapsulated or coated active compound is distinguished in
particular by the fact that a mixture of essentially native starch and
at least one agent at least partially swelling the starch is used as an
encapsulating or coating carrier substance for its preparation and, for
25 encapsulation or coating, is mixed together with the active compound
and at least one emulsifier.
The methods according to the invention described above are in
particular suitable for encapsulating or coating pharmace~ltical active
30 compounds and/or for the production of medicaments or medicinal
indications .
The method according to the inveniion is moreover of particular
interest for encapsulating water-soluble or water-miscible substances,
35 in particular water-soluble vitamins and citric acid.
The methods are additionally suitable for the encapsulation or
coating of adhesives, flavourings, fragrances, detergents, pesticides,
.
- 9 -
herbicides, dyes, synthetic resin additives, building material additives,
concrete additives and/or reactants for the coating of carbon-free
copying papers.
As representative of these areas of application, specific
reference may be made to the use of the method according to the
invention for ~he encapsulation of concrete additives, such as wetting
agents, hardening regulators, synthetic resin additives etc., whose use
is difficult as a result of their existence as highly viscous or viscous
0 liquids. They carmot be added, or cannot be added in metered form, to
the dry cement, and on adding to the wet cement their reaction is
immediately started.
In contrast, the dry, pulverulent starch/active compound
l S mixture can easily be admixed with the dry cement, both metering
and also subsequent storage of the cement duTing a relatively long
period of time being unproblematic. The additives become in each
case active on adding water.
At this point reference may be made to the literature citations
with respect to the production and use of microcapsules which have
been mentioned as prior art in the introduction and in which
extensive applications of microcapsules are mentioned. In this
connection, reference may additionally be made to Ullmann's
2s Encyclopedia of Industrial Chemistry, 5th Edition, Vol. A S, where on
pp. 518 ff. reference is made in detail to possible additives for the
preparation of concrete, for whose encapsulation the methods
according to the invention mentioned above are also suitable.
3 0 The invention described above will now be illnstrated in greater
detail with reference to the appended S exarnples of the encapsulation
of vitamin C.
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- 10 - ~ ~ J ~ 3
Encapsulation of vitamill C:
Example l:
4 kg of native potato starch are extruded with 2.5 kg of a
mixture composed of the following components:
- 77.6% of glycerol,
- 15.5% of triglycerol (Miglyol 812),
- 6.9% of emulsifier (Tween 80 from ICI)~
10 using a kneading extruder (Buss, Pratteln, Switzerland) during the
course of one hour. The water content of the starch in this case was
about 12%. The following process conditions were chosen in the
kneading extruder: -
- Spindle temperature 110C,
lS - Heating zone 1: 113C,
- Heating zone 2: 116C,
- Heating zone 3: 122C,
- Speed: 140 revolutions/min.,
- Power consumption: 0.6 kw.
A flaky white powder was formed as the product, individual
grains, which are swollen with glycerol, being clearly detectable under
the microscope.
A mean particle size of about 100 ,um is achieved by
homogenising in the kneader. Due to the oil used, aglommeration of
the starch polymer spheres is prevented. Other starches can of course
also be used as the polymer, which in the present example is potato
starch.
20% of vitamin C was added to the powder obtained in the
above manner and kneaded in with the same parameters during a
3 second passage through the kneader. The result can likewise be
clearly seen under the microscope. The largest part of the vitamin C
35 crystals is embedded in the élastic bodies. If, for example, the grains
are pressed flat, the embedded vitamin C crystals can be detected
therein under the polarising microscope.
3 ~i ~J ~
Other active compounds can also be incorporated into these
elastic grains. The only condition is that a certain affinity of the active
compound for the polar glycerol starch must be present, i.e. the active
compound must be wettable by the glycerol starch mass.
Example 2:
The same composition as under 1), but allowed to stand
overnight (not extruded). 12 hours later, a swollen powder is likewise
10 obtained, into which vitamin C is kneaded. This experiment shows
that the increase in the temperature only accelerates swelling, but is
not a condition that swelling takes place. The vitamin C is
incorporated as in the fiTst example using the Buss kneader.
15 Exam~le 3:
40 g of starch (water content: 12%) and 25 g of the mixture from
Example 1 ) are kneaded for about 2 minutes in a Brabender
laboratory kneader (70 g batches) and 16 g (20%) of vitamin C are
20 then added and the mixture is kneaded for a further 2 minutes. The
vitamin C is kneaded into the starch grains to more than 90%. Further
experiments with 30% or 40% of vitamin C also give po~itive results,
and the percentage of non- encapsulated vitamin C only rises slowly.
2s Example 4:
16 kg of native potato starch (water content: 5%) are swollen
with 10.8 kg of the same mixture as above in a synchronised double
spindle extruder at 150C. 20% of vitamin C is added to this powder in
` 30 a tumbler mixer and the mixture is then extruded again at 140C in
order to knead in the vitamin C.
Example 5:
- 35 The same conditions as under l~xample 4), only ca~ried out in
one step. The screw configuration of the extruder is modified in such a
way that during entry starch and emulsion are mixed and swollen to
give powder and vitamin C is added directly to the centre of the
- 12- ~ 3~
extruder. At the end, a fine powder of encapsulated vitamin C is
obtained which does not additionally have to be subsequently treated
(grinding, sieving, etc.).
The abovementioned examples of the encapsulation of vitamin C
by glycerol/starch are only used to explain the method according to
the invention, which of course can be modified in all sorts of ways, as
disclosed in detail in the description.
Thus, the method is also suitable for encapsulating other
vitamins, pharmaceutical or cosmetic active compounds, o-f particular
interest being encapsulation or coating of or with water-soluble or
with water-miscible substances, such as7 in particular, water- soluble
vitamins and, inter alia, with citric acid. As representatives, some
15 active substances have been processed according to the method
according to the invention in the following Example 6, it being
possible, of course, to extend the list of possible active substances in
the most varied manner.
20 Example 6:
As mentioned above, various active compounds were
incorporated into swollen or thermoplastically processible starch,
comprising about 27% to 30% of glycerol. The practical procedure was
2s carried out at 140C in a so-called Brabender kneader, 70 g batches
being employed analogously to the examples described above.
Riboflavine (vitamin B2), pyridoxine (vitamin B6), nicotinic acid,
methionine, citric acid, thia~nine NO3 (nitrate) and lysine HCl were
3 0 used as active compounds.
Basically, the active compounds described can be incorporated
into the swollen starch analogously to vitamin C, as described in
Example 5, in order to form a fine powder of encapsulated active
3s compound.
As the active compounds mentioned behave like fillers in
industrial polymers, extrusion of these active compounds into a
.
- 13-
swollen starch mel~ is also possible, the colTesponding melt, the
fluidity of the melt and the subsequent cuttability being investigated
or listed in Table I which follows.
Table I
Substance % bv ~. hlelt Dec~m~o- Tacki- Extrusion
of active sition ness
çs~m p .
- Riboflavine(B2) 20% ~+,yellow none d,h,b
Pyridoxine(B6) 30% ~ possible gummy +
Nlcotinic acid 20% ++,viscous none d,~
Me~hionine 20% ++,brown possible d,~
Citric acid 2û% ~ n o n e d,+~
Thiamine NO3 20% ++,yellow possible d,~ +
Lysine HCI 20% rubbcr none t,~
~: ~ good
very good
' 20 d dry
. h hard
b brittle
t tacky
. .
The results presented in Table I have only rest~icted validity
in this respect, as when using additional additives in the melt the
statements can appear completely different.
~s already mèntioned above in the description, the method
according to the invention is not only suitable for the coating of
` medicinal, cosmetic or pharmaceutical active compounds, but also for
the encapsulation and coating of dye additives, foodstuff additives,
concrete additives, detergent additives etc.
3 s As representatives of this almost unrestricted glOUp of
: possible additives, the invention will be explained in greater detail in
the following, for example, with reference to a foodstuff additive and
concrete additives.
:
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- 1 4 ~ ~ ~3
Example 7: Lemon flavour
Up to 40% by weight of lemon flavour are kneaded in cold
5 form with dry starch. The lemon flavour emulsion contains very
volatile components, which would evaporate on increasing the
temperature. The emulsion is absorbed into the starch within 2 min.,
and a yellow powder is formed which smells less intensively of
lemon than the emulsion itself. If the powder is heated, it
O immediately begins to adhere and forms pearl grey lumps.
The advantage of the powder prepared in this way compared
to the emulsion itself is that the powder can be very simply
reprocessed and in particular can be very easily metered. The
15 emulsion used hitherto, on the other hand, is not stable and it must
be stirred again and again. Moreover, the emulsion dries out rapidly
- and loses the flavour if it is allowed to stand in the open. In contrast,
the powder hardly loses the lemon flavour.
20 Example 8: Concrete additives
The concrete additives are usually highly viscous or viscous
substances which can be metered only poorly and in particular
cannot be admixed homogeneously to the dry cement. If the concrete
25 additives are only added to the already made-up aqueous cement,
their activity is immediately initiated and the cement must be
processed immediately.
The concrete additives investigated in connection with the
30 method according to the invention are
- Rheobuild 1000, a naphthalene sulphonate (Na salt), SO4-Na,
- Rheobuild 2000~ a melamine derivative of the following
- formula:
N~2
I
c~
N N
11 l
C C
/\ ~\
2 N NH 2
where 1 or 2 -NH2 can be replaced by -Cl or -OH or alkyl,
- Rheobuild SV 87056, a polycarboxyl compound based on
polyacrylic acid Na salt or a copolymer of acrylic acid esters
and free acrylic acids and their Na salt,
15 - Beclcopox EH 623, an amine epoxide hardener, and
- Rutapox EH 4000, an epoxy resin.
All the concrete additive active compounds mentioned are
commercial products and can be obtained from Masterbuilders
Technologies Europe AG, Ifangstrasse 11 in 8952 Schlieren/
Switzerland .
These liquid concrete additives can be easily kneaded Y.rith dry
starch withou~ additional swelling agent, such as glycerol or
aminoethanol. Glycerol in addi~ion could not be used because of its
incompatibility with concrete. Obviously, in the present cases the
active compound itself also still forms the swelling agent for the
swelling of the starch. After at most 2 min. with heating if necessary,
the liquids are absorbed in the starch, this occasionally taking place
~` 3 0 with evolution of heat.
If aminopropanol or ethanol is additionally employed as the
swelling agent, the swelling should be started in the cold in order
`~ that the starch does not form a paste, or else an emulsifying oil must
:` 35 be added as in the examples described above with respect, for
example, to vitamin C.
.
, , ~ , , ,~
. . , , ~ , - .
, ., , -, ,
- 1 6 - 2 ~ c~ ~Ç; ~
The active compounds according to Examples 7 and 8 are
represented in tabular form in the followingTable II, in which their
behaviour on swelling or absorption into the starch has likewise been
more closely investigated.
Table II
Tyge Swell_ng Soluble Mixin~ Process
agent for in aminQ~ ratio Description
starch ethanol
Lemon yes, only 30 40% only
flavour cold (20C) cold
kneaded
Rheobuild no yes max.30% hot
1000 kneaded
Rheobuild yes, but cold max.30% hot
2000 kneaded
Rheobuild
SV 87056 yes, heat yes max.30% hot
(140C) kneaded
Beckopox yes, good yes 20% hot
EH 6~3 kneaded
Rutapox yes yes 20% hot
EH 4000 kneaded
2s The active compounds described in Examples 1 to 8 are
representative of a nearly unlimited list of possible active compounds
and substances which can be encapsulated or coated by the method
according to the invention. The encapsulation and coating method
itself can also be changed or modi~led in any desired ways.
It is essential for ~he method according to the invention to use
~` native starch, a swelling agent at least partially swelling the native
starch and, under certain circumstances, an emulsifier, where the
active substance must be wettable by the swelling agent/starch
` 35 phase. It is thoroughly possible here that the active compound itself`~ serves as the swelling agent. An oily substance is preferably
additionally used
:
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