Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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F097/CAS 196
The pre~ent invention relate3 to microcap~ules
containing water~oluble amphiphilic substances and to
a process enabling their production.
Microcapsules are particles of ~pherical shape,
who~e size range~ between 1 and 1250~ , constituted by
a qupport material, containing the encapsulated
sub~tance. According to the structure of the ~upport
material, two type~ of microcapsules are to be
distinguished:
- microcapqules of ~he reservoir type of which
the support material i~ a solid envelope, of
variable thicknes~ containing the ~ubstance to
be encap~ulated,
- microcap~ule~ of the matrix type also known
as microqpheres in which the ~upport material
i~ a continuou~ network, in which the
~ubstance to be encapsulated is dispersed.
In the sense of the pre~ent invention, the term
microcapsule encompasse~ both microcapsules of matrix
type and microcapsule~ of reservoir type.
The support material limit~ exchanges between the
encap~ulated ~ubstance and the outer medium~ whlch ha~
the effect of protecting ~aid sub~tance, and of
permitting its incorporation in products into which it
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would not have been po~sible to incorporate it ln the
free ~ate. In addition, the u~e of micro-
encap~ulated ~ub~tance~ enable~ the release of the
latter to be controlled at a different moment - the
substance i~ then relea~ed by destruction of the wall
of the microcapsule - or by ~preading it over time -
the ~ub~tance is relea~ed by gradual diffu~ion through
the ~all -.
Many sub~tance~ may be encapsulated: they may be
chemical products ~uch a~ medicament~ or pesticides,
or macromolecules ~uch a~ enzymes and also living
cell~.
Microcapsules are used in many field~ ~uch as
pharmacy, bio-indu~try, co~metic~, the farm produce
indu~try, the paper indu~try, etc...
Example~ of u~es of microencap~ulation are
described in detail in the article of C. DUBERNET and
J P BE~OIT which appeared in "L'Actualite Chimique" ;
(Deccmber l986).
One of the proces~e~ used to encap~ula~e liquid
~ubstances i~ microencapsulation by interfacial
polycondensation. Interfacial polycondensation i~ a
polymeri~ation reaction which i~ produced at the
interface of two immiscible llquid~, of which at lea~t
one of the two contains a suitable polyfunctional
reagene. In the case where this reaction occur~
without the formation of byproducts, it i~ al80 called
interfacial polymeri~ation. This reaction may be
carried out in an emul~ion, at the interface between
the two pha~es. In thi~ ca~e, it re~ultY ln the
formation of re~ervoir microcap~ules, if the oligomer~
formed at the start of the reaction are insoluble in
: the disper~ed phase, and mstrlx microcapsuleY if the
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oligomers are soluble in the disper~ed pha~e.
Thi~ proces~ which has been de~cribed, for
example, in French patent 1 427 085 and, more recently
in the publication of R ARSHADY, /J~
MICROENCAPSULATION 1989, Vol. 6 Nl/, as well a3 in
the publication of C DUBERNET and J BENOI~ ment-Joned
above9 enable~ the preparation of capsules who~e wall
is formed of polyamide, polyurethane, polyurea,
polyester, etc
Belgian patent 796 746 describe~ also a proce~s
for producing, from an oil/water emulsion
microcapsule3 who~e wall is formed of polyurea9 by
polymeri~ation of an isocyanate, present in the
organic phase. French patent 2 548 046 describes a
process based on the same principle, for the
encapsulation of watersoluble substances, from a
water/oil 2mulsion.
The~e processe~ are ~uitable for encap3ulation of
many hydrophilic or lipophilic substance~. ~owever,
they do not enable the encap~ulation of water~oluble
amphiphilic ~ub~tance~ ~uch a~ 5 for example, the
quaternary ammoniums.
Now quaternary ammoniums are used among other
thing~ for their antiseptic properties. For example,
benzalkonium chloride is used ln topical application~,
as a bactericide and fungicide. Its action on the HIV
viru~ has also been demon~trated. ~owe~er, the
` quaternary ammonium~ are incompatible with many
~ub~tances, particularly anionic substances such as
soap~. In addltion, they are commonly used in
solution, which doe~ not permit associatlng them
conveniently with a ~olid ~upport. It would therefore
be partlcularly advantageous to encap~ulate them.
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However, this encap3ulation po~es specific
problem~ ~hich had not been re~olved until now.
The quaternary ammoniums being watersoluble, it 1~
neces~ary to encapsulate them, to obtaln a stable
emulsion of the water in oil type. Now the quaternary
ammoniums and more generally, watersoluble amphiphilic
sub~tance~ favour emulsions of the oil in water type,
`` and destabilise emulsions of the water/oil type. In
addition, it i~ known tha~ the quaternary ammoniums
interfere with the interfacial polymerisation
reaction. Thus, for example McGINITY et alO/J.
Pharm., 70, 372 (1981)/ and ARS~ADY / J.
Microencapsulation, 6, 18-23, 1989/, con~ider that it
is not pos~ible to obtain microcap~ules in the
presence of quaternary ammonium.
Now the inventors have developed a proces~ which,
surprisingly, enables the production of microcapsules
containing watersoluble amphiphilic sub~ances,
including quaternary ammonium~.
It is accordingly an object of the present
invention to provide microcapsules, characteri~ed in
that they contain at least one watersoluble
amphiphilic substance.
According to a preferred embodiment of these
; 25 microcapsule~, the water~oluble amphiphilic substance
is a cationic substance, in particular a quaternary
: ammonium.
According to a particularly advantageous modality
~` of this embodiment, the water~oluble amphiphilic
substance i~ benzalkonium chlorlde.
According to another preferred embodiment of the3e
microcapsules the water~oluble amphiphilic substance
is a non-ionic ~ubstance, in particular a water
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soluble polyoxyethylene derivative~
According to a partlcularly advantageou3 modalit~
of ~hi~ embodiment the watersoluble amphiphilic
substance is a nonoxynol whose average number of
- 5 ethylene oxide unit~ per molecule i~ greater than 6.
According to a particularly advantageous modality
of this embodiment the watersoluble amphiphilic
substance is an octoxynol whose average number of
ethylene oxide units per molecule is greater than 6.
According to another preferred embodiment of the
pre~ent invention, the watersoluble amphiphilic
~ubstance i~ an anionic sllbstance, in particular a
~odium alkyl sulfate.
According to a particularly advantageou~ modality
of thls embodiment the water~oluble amphiphilic
sub3tance is ~odium lauryl ~ulfate,
According to another preferred embodiment of the
pre~ent invention9 the wall of the microcapsules is
constituted essentially of polyurea. It can al~o be
constituted of any other polymer resulting from a
polymerisation or interfacial polyconden~ation
reaction, such a3 for example polyamide polyester3 or
polyurethanes.
It is in addition another object of the pre~ent
invention to provide a proce3s of encapsulation of
watersoluble amphiphilic substances, by
polycondensation or by interfacial polymerisation,
which compri~e~ a first step of production of an
emulsion of an aqueous phase containing the ~ubstance
to be encapsulated in an organic phase, and a second
step of formation of microcapsules by polymerisation
of one or ~everal polyfunctional reagents, which
proces~ is characterized in that the aqueou~ phase
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containing the amphiphilic ~ub~tance to be
encapsulated i~ emulsified in the presence of a
-- suitable emul~ifying agent, in an organic pha~e
containing a~ lea~ one component taken from the group
con~ti~uted by aliphatic, alicyclic or aromatic
hydrocarbons, halogenated or not, and triglyceride~
According to a preferred embodiment of the proce~
~- according to the pre~ent invention, the HLB
(hydrophile lipophile balance) of the emulsiEier i9
le~ than 7. An ELB le~s than 7 can be obtained by
using as the emul~ifier either a ~urface active agent,
or ~everal surface active agents po~sibly as~ociated
with agents lowering the HLB, such a~ carboxylic acid
~alts, like for example sodium or lithium acetate or
formate.
According to an advantageou~ modallty of this
embodiment, the emulsifier i~ a copolymer of modified
non-ionic polyester type, of HLB compri~ing between 5
~` and 7.
According to another advantageous modality of thi~
embodiment, the emul~ifier i~ con~tituted by a
mixture 9 in solution in the organic phase, of a
poly~iloxane (for example the polysiloxane 3225C) and
a ~orbitan ester (for example Span 85).
According to yet another advantageous modality of
thi~ embodiment, the emul~ifier i~ con~tituted by an
association of Polyqorbate 80, in sQlution in the
aqueou~ pha~e, and a ~orbitan ester (for example Span
85), in ~olution in the organic phase.
According to another preferred embodiment of the
proces~ according to the present invention, the
`~ organic pha~e contain~ a mixture of triglycerides.
According to another embodiment of the process
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accoridng to the present invention, the one or more
`~ triglycerides contained in the organic pha~e is/are
one or more triglyceride(s) of C8 to Cl~ fatty acids.
According to yet another embodiment of the process
according to the present invention, the organic phase
is con~tituted by a chloroform/cyclohexane mixture.
According to yet another embodiment of the proce~s
according to the pre~ent invention, the organic phase
contains xylene or toluene.
10The process of encap~ulation according to the
pre~ent invention may also be employed in an organic
pha~e con~tituted exclu~ively by triglycerides.
Applicants have in addition ob~erved that by
varying the re~pective proportions of hydrocarbons and
of triglycerides, it is possible ~o obtain capsule~ of
; variable strength, which can hence be adapted to
various uses.
~- According to a preferred embodiment of the process
according to the pre~ent invention, the organic pha~e
is a hydrocarbon/triglyceride mixture which contains
between 10 and 50%, by weight, of hydrocarbons.
The majority of polyfunctional reagents
customarily used in the interfacial polymerisation
proce~ses may be used in the proce~s according to the
psesent invention, for the formation of the wall~ of
the microcap~ule~.
For example diisocyanates may be u~ed to obtain
microcap~ules of which the wall i3 e~sentially
constituted of polyurea.
The microcapsules according to the present
invention may generally be u~ed in all applications of
microcap~ules. Without being limiting they may be
incorporated in liquid~, pastes, creams, soaps, paints
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and varnishe~ or solid material~ such a~ paper~,
textile~, ~ponges, materlal~ bas2d on polymer~, in
partlcular ela~tomers.
In the accompanying drawings:
Figure 1 qhow~ the appearance of the cap~ule~
obtained; and
Figure 2 ~hows the percentage of residual water ln
the microcap~ule~ a~ a function of the tlme of
pre3ervation .
The present in~vention will be better under~tood by
means of the additional de~cription whi~h follow~,
which refer~ to examples of the preparation of
microcapsule~ following the proce~s according to the
invention.
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EXAMPLE 1
A) ORGANIC PHASE
15g of diphenylmethane diisocyanate and 6g of A 60
are disolved in 608 Of xylene, 140g of mygliol 812
were then added. (The A 60 [ICI Laboratories] i9 a
non-ionic ~urfactant; it i~ a modified polyester.
Mygliol 812 i~ a mixture of triglyceride~ of ~aturated
and fractionated fatty acid~ of COCO, with C8 - CLo
chain length).
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: B) AQUEOUS PHASE
"` 0.3g of benzalkonium chloride are disolved in 30ml
~`~ of water.
The aqueou~ pha~e i~ emul~ified in the organic
phase by mean~ of a high power microvortex for 1 to 2
minutes. ~he emulsion so prepared i~ placed with
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gentle stirring (blade, 300rpm) for the duration of
the reac~ion ~8 to 10h). ~he mlcrocapsules obtained
are recovered after decantation. They are then washed
wi~h cyclohexane then dried at ambiant temperature.
45g of microcapsules of size comprised between 30 and
50~m are thu~ obtained The amount of encap~ulated
- benzalkonium chloride i~ determined by ~PLC according
to the following ~echnique: a predetermined amount of
microcapsules disolved in 5ml of Dimethyl formamide.
5ml of water are added to the solution to re-
precipitate the polymer. The resulting suspension
undergoes centrifugation a~ 35~000 rpm or lh30. The
supernatant after passage over a filter of 0.2~m i~
determined by HPLC according to the following
operational modalities: 30 1 of specimen are analysed
by passage over a NOVAPACK CN (WATERS) column with a
mobile phase compo ed for 60% of acetonitrile and 40%
of an acetate buffer, at a flow rate of 2ml/min. The
detection of the peak corre~ponding to the
benzalkonium chloride i9 done at 254nm. The
encapsulation yield of the benzalkonium chloride,
determined according to thl~ method is 40%.
Figure 1 ~hows the appearance of the cap~ules
obtained, observed with the ~weep electron ~icro~cope.
EXAMPLE 2
A) ORGANIC PHASE
15g of diphenylmethane dii~ocyanate and 12g of A
60 are disolved in 40g of xylene to which are then
i 30 added 240g of MYGLIOL 812.
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B) AQUEOUS PHASE
3g of benzalkonium chloride are disolved in 30ml
of water. The re~t of the procedure i~ identical with
that described in Example 1.
40g of microcap3ule~ of a ~lze comprised between
50 and 70~m are recoveredO The encap3ulation yield i~
60% namely 46mg of benzalkonium chloride per lg of
cap~ule3 .
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EXAMPLE 3
A) ORGANIC PHASE
7g of diphenylmethanedii30cyanate and 4g of A 60
are disolved in 30g of toluene. 170g of MIGLYOL 840
are added to the solution.
B) AQUEOUS PHASE
0.3g of benzalXonium chloride are di~olved in 30ml
of water.
The re~t of the procedure is identical with that
de~cribed in Example l. l3g of microcap~ule~ ar~
recovered.
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EXAMPLE 4
A) ORGANIC PHASE
15g of diphenylmethane diisocyanate and 7.5g of
Span 85 are di~solved in 30g of xylene, to which are
added 170g of MIGLYOL 812.
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B) AQUEOUS PHASE
2,5g of Tween 80 and 0.3g of benzalkonium chloride
are di3~01ved in 30ml of water. The whole is
emulsified in the preceding mixture~
The re3t of the procedure is identical with that
descrlbed in Example 1. 18g of microcap~ule~ are
recovered.
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EXAMPLE 5
A) ORGANIC PHASE
lOg of diphenylmethanediisocyanate and 5g of A60
are dissolved in 40g of xylene, to which are added
160g of MIGLYOL 812.
B) AQUEOUS PHASE
lg of sodium laurylsulfate are dissolved in 30ml
of water.
The rest of the procedure is identical ~ith that
described in Example 1. The microcap~ule~ have an
average size of 10~.
EXAMPLE 6
A) ORGANIC P~ASE
15g of diphenylmethanediisocyanate and 7g of A60
sre dis~olved in 200g of xylene.
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" B) AQUEOUS PHASE
3g of Triton X 100 are dis~olved in 30g of water.
" 30 The re3t of the procedure is identical with that
described in Example 1. The ~ize of the microcapsules
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EXAMPLE 7
A) ORGANIC PHASE
15g of diphenylmethane diisocyanate, 5g of
poly~iloxane 3225C (DOW CORNING) and 5g of Span 85 are
di~olved in 200g of xylene.
B) AQUEOUS PHASE
3g of Nonoxynol 9 are dis~olved in 30ml of water.
The re~t of the procedure i~ identical ~ith that
` 10 de~cribed in Example 1.
EXAMPLE B
A) ORGANIC PHASE
lOg of diphenylmethane diisocyanate and 5g of A
60 are dissolved in 200g of a cyclohexane/chloroform
mixture in a ratio 4/1.
B) AQUEOUS PHASE
lg of benzalkonium chloride i~ di3solved in 30ml
of water.
The re~t of the procedure i~ identical ~ith that
described in Example 1.
INFL~NC~ 0~ ~H~ ORG~IC PHAS~ 0~ TH~ PROP~RTI~S
OF THE MICROC~PS~L~S
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A) INFLUENCE ON THE MECHANICAL PROPERTIES
Table 1 below ~hows the influence of the
~; composition of the organic pha~e on the mechanical
``` strength properties of the mlcrocapsule~ prepared from
a 1% solution of benzalkonium chloride,
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TABLE 1
ORGANIC PHASE STRENGTH
5 XYLENE 100~ 0
XYLENE 80% MYGLIOL 20~ 0
XYLENE 60~ MYGLIOL 40~ 0
XYLENE 50~ MYGLIOL 50~ 0
XYLENE 40~ MYGLIOL 60%
15 XYLENE 30% MYGLIOL 70% +~+
XYLENE 15~ MYGLIOL 85
MYGLIOL 100%
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The key to thi~ table i8 the following:
Very fragile microcap~ule~ 0
Fragile microcap~ules
25 Strong microcapsules
Very strong microcapsule~ +~
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~B) INFLUENCE ON THE WATER CONTENT OF THE
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MICROCAPSULES AND ITS CHANGE IN THE COURSE OF TIME
`~`The water content is evaluated by measuring the
`~ weight loss on drying by heating in the oven for one
~; hour a~ 105 C.
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Figure 2 shows the percentage of residual water ln
the microcapsule~ as a function of the time of
preservation for microcapsules prepared from a 1%
- solution of benzalkonium chloride, in 3 lipid phases
of different composition
~ --~ XYLENE i5% ~IYGLIOL 85~6
- ~_ XYLENE 40% MYGLIOL 60~6
~ MYGLIOL 100%
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