Note: Descriptions are shown in the official language in which they were submitted.
CA 02238263 1998-0~-21
E -- 1 --
Cortisol Spray
The present invention relates to a pharmaceuti-
cal composition for the dermal application of hydro-
cortisone or a derivative thereof, a method for manufac-
ture of this pharmaceutical composition as well as its
application in therapy.
The body specific glucocorticoid hormone
(cortisol), Merck Index Eleventh Edition fl989) No. 4710,
page 4711, chemical description~ 11, 17, 21-trihydroxy-
pregn-4-en-3,20-dion, is dermally administered as an anti-
inflammatory agent for treating inflammatory diseases,
e.g. eczemas, psoriasis, dermatitis, contact allergies
etc. The Index Nomi~um 1992/93, Swiss Pharmaceutical
Society, Medpharm, Scientific Publ. D-Stuttgart lists for
the active ingredient hydrocortisone 81 dermal preparat-
ions with registered trademarks. Of the derivatives, in
particular the 21-acetate there are likewise known numer-
ous preparations.
Since the mentioned inflammatory skin diseases
can be resistant and protracted, a dermal preparation
should be suitable for administering over a longer period
of time. With the prolonged application of glucocorticoids
on the skin in spite of a good e~fectiveness and provable
healing successes, systemic effects and side effects are
CA 02238263 1998-0~-21
problematic, for this see section G10 in Rote Liste 1994,
Arzneimittelverzeichnis des BPI (Bundesverband der Pharma-
zeutischen Industrie), ECV Editio Cantor, D-88322 Aulen-
dor~, No. 64009. Numerous dermal p~reparations therefore,
instead of one of the highly effective new active ingredi-
ents of the glucocorticoid type described numerously in
the literature, contain only the more weakly effective
hydrocortisone which has been known for a long time and
this even further in an extremely small dosage, e.g. most-
ly 1 mg per gram of formulation. One has thereforeattempted to improve the lower effectiveness of such prep-
arations by increasing the dosage. Preparations with a
higher dosage even of hydrocortisone must however due to
the known side effects and the numerous counter indi-
cations be subjected to medical control and mandatory pre-
scription.
It is therefore the object of the invention tomanufacture for the well-tried active ingredient
hydrocortisone a dermal preparation with an improved
effectiveness with a smaller dosage.
In the narrower sense, it is the object of the present
invention to manufacture for the active ingredient
hydrocortisone an improved dermal preparation which is
suitable for releasing without prescription as a so-called
OTC preparation (Over-the Counter preparation) within the
framework of the so-called self-medication.
CA 02238263 1998-0~-21
The achievement of the object is based on the
consideration that by increasing the solubility of the
active ingredient hydrocortisone in the formulation base,
an improvement in effectiveness with an unchanged low con-
centration is to be achieved. Hydrocortisone itself isweakly soluble in water which in dermal formulations is a
considerable constituent. The Merck Index, loc, cit., ind-
icates a water solubility of 0.28 mg/ml (25~C). In ethanol
the active ingredient is more soluble: 15 mg/ml (25~C).
The addition of large quantities of ethanol for improving
the solubility of the active ingredient is not suitable
for dermal preparation, since ethanol for other constitu-
ents of the formulation likewise acts as a solvent and
encourages the drying of the skin. Alternatively to the
application of an unsuitable solvent numerous publications
suggest aqueous finely dispersed systems with dissolving
properties based on lipid mixtures. Herein the insoluble
active ingredient is enclosed in lipid particles with a
particle size of less than 1 ~m, which with the aqueous
carrier fluid form a colloid-dispersed or finely dispersed
system, which although does not represent an true molecu-
lar dispersed solution, is however sufficiently homogene-
ous for a dermal formulation. In the literature on the
subject there is mentioned the encapsulation of lipophils
and/or weakly soluble active ingredients in micelles,
mixed micelles, reverse micelles, unilamellar or multi-
lamellar liposomes, nanocapsules, nanoparticles etc.
CA 02238263 1998-0~-21
- 3a -
The document DE-A-4018995 describes the incorporation of
corticosteroids into an amphiphillic, non-ionic lipid
phase, which in an aqueous phase ~orms vesicles with a
size of 10 to 5000 nm. The docume1t W0-A-93/18752
describes compositions for the dermal application of phar-
maceutical products with particles from an oily fluid,
from an emulsifying agent, e.g. a phospholipid, and from a
non-ionic tenside. The particles have a size of 50 to 500
nm which in the examples in the document are achieved by
treatment in a homogeniser. For the oily fluid as well as
for the emulsifying agent and the tenside in each case
there are mentionefl numerous possible substances in the
document.
CA 02238263 1998-0~-21
It has been surprisingly found out that a
lipophile formulation base consisting of partial fatty
acid ester of polyoxyethylene sorbitan, of a phospholipid
and of a neutral oil is suitable for manufacturing a par-
ticularly homogeneous finely dispersed nanodispersion ofthe active ingredient hydrocortisone. The present inven-
tion has as the subject-matter a pharmaceutical composi-
tion for the dermal application of a corticoid, which has
the following constituents:
a) the active ingredient 11, 17, 21 -trihydroxypregn-4-en-
3,20-dion (hydrocortisone) or a derivative thereof, where
appropriate in combination with a wound healing agent;
b) at least one partial fatty acid ester of polyoxyethyl-
ene sorbitan or a combination thereof;
c) at least one essentially pure phospholipid of the for-
mula:
CH2--O--Rl
21 (I)
31
CH2-O-:'-O-R3
OH
where Rl indicates C1020-acyl, R2 hydrogen or Cl0_20-acyl, R3
hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, Cl4-
alkyl, Cls-alkyl substituted by carboxy, C2_s-alkyl substi-
-
CA 02238263 1998-0~-21
tuted by hydroxy, C2_s-alkyl substituted by carboxy and
hydroxy or C2_5-alkyl substituted by carboxy and amino, the
inositol or glyceryl group, or salts of these compounds;
r
d) a triglyceride of the formula:
C~Z-O-Rl
CH-O-Rz (II)
1~' 1 ..
CH2--O-R3
where Rl,R2 and R3 indicates C8_24-acyl;
e) water as a carrier fluid in the purity required for the
transdermal application; and where appropriate
,
f) aiding agents suitable ~or dermal forms of administra-
tion.
This pharmaceutical composition is distin-
guished by favourable phase properties of the solubilised
active ingredient. Thus with a present opalescence and
transparency in counter light it is only to be recognised
by an extremely slight milky murkiness that the suspension
still has physical differences with respect to the ideal
condition of a pure molecular solution. Electron micro-
scope imaging shows that a population of more than 98% of
the active ingredient is present in a Gaussian distribu-
tion as a dispersion of particles (nanoparticles) with aparticle size of less than approx. 50 nm (nanodispersion).
-
CA 02238263 1998-0~-21
These differences with respect to a pure solution are how-
ever acceptable on account of the particularly good homo-
geneity properties of the dispersion, which for example
can be detected by a surprisinglyrhigh storage stability,
e.g. no segregation after a storage lasting several months
at temperatures of up to room temperature (the stability
to be expected by extrapolation is longer than two years).
All these properties may be achieved without the
additional application of a homogeniser by way of a simple
mixing of the constituents.
A preferred embodiment form concerns a pharma-
ceutical composition containing:
a) the active ingredient hy,drocortisone or the 21-acetate,
where appropriate in combination with dexpanthenol;
b) the composition consistin~ of polysorbate 20, 80 and
60;
c) purified lecithin from soya beans;
d) a triglyceride from the group of neutral oils; and
e) water as a carrier fluid in the purity required for the
dermal application; and where appropriate
f) aiding agents suitable for dermal forms of administra-
tion.
The active ingredient hydrocortisone - compo-
nent a) - in the pharmaceutical composition described
nearer the beginning is contained in the dosage allowable
CA 02238263 1998-05-21
- 6a -
for the dermal application. In the commercial formulation
according to the Rote Liste or Arzneimittelkompendium der
Schweiz, Documed Basel, Schweiz, .in prescription-free pre-
CA 02238263 1998-0~-21
parations there is contained a dose of approx. 0.1 to 0.5%
(calculated with respect to free hydrocortisone).
A derivative of hydrocortisone is in particular
the 21-acetate, 21~acetate-17-propionate (aceponate), 21-
bendazac, 17a-butyrate, 17a-butyrate-21-propionate, 21-
cipionate (cyclopentane propionate), 21-disodium phos-
phate, 21-hydrogen succinate, 21-sodium succinate, 21-
tebutate (tert. butyl acetate), 17-valerate or xanthogen-
ate.
The active ingredient hydrocortisone or one of
the mentioned derivatives may in the pharmaceutical compo-
sition be contained in combination with a known wound
treating agent or epithilisation agent, e.g. dexpanthenol.
The component b) - partial fatty acid ester of
polyoxyethylene sorbitan - consists preferably of an
essentially pure or mixture of various esters of sorbitan,
wherein the structure of the fatty acid groups and the
length of the polyoxyethylene chains vary. The sorbitan is
preferably ethered by three hydrophillic polyoxyethylene
chains and estered by a hydrophobic fatty acid group. The
sorbitan may however also be ethered only by one or two
hydrophillic polyoxyethylene chains and accordingly est-
ered by three or two hydrophobic fatty acid groups. In
total the sorbitan base body is substituted by at least
one to at most three hydrophillic polyoxyethylene groups
CA 02238263 1998-0~-21
and accordingly by at most three and at least one
hydrophobic fatty acid group.
The polyoxyethylene chain is straight-chained
and comprises preferably 4-10, in particular 4-8, ethylene
oxide units. The ester groups on the sorbitan base body
are derived from a saturated or unsaturated, straight-
chained carbon acid and an even number of 8-10 C-atoms.
The ester group derived from this carbon acid is preferab-
ly straight chained with 12, 14, 16 and 18 C-atoms, e.g.
n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octade-
canoyl. The ester yroup derived from an unsaturated carbon
acid with an even number of 8-20 C-atoms is preferably
straight-chained with 12, 14, 16 and 18 C-atoms, e.g.
oleoyl. The mentioned esters of sorbitan, fulfil the
details mentioned in the British Pharmacy list (special
monograph) or Ph. ~Ielv. VII. There applies in particular
the product descriptions published by the mentioned manu-
facturers with the details of data sheets for the product
concerned, in particular specifications such as form, col-
our, HLB-value, viscosity, rising melting point and solu-
bility.
Suitable partial fatty acid esters of polyoxy-
ethylene sorbitan are commercially obtainable under the
name Tween~ of the company ICI and known under the chemi-
cal description po]yoxyethylene (20 or 4)-sorbitan mono-
laurate (TWEEN 20 and 21), polyoxyethylene-(20)-sorbitan
CA 02238263 1998-0~-21
monopalmitate or monostearate (TWEEN 40 and 60), polyoxy-
ethylene-(4 or 20)-sorbitan-monostearate or tristearate
(TWEEN 61 and 65), polyoxyethylene- (20 or 5)-sorbitan
monooleate (TWEEN 80 or 81) or polyoxyethylene-(20)-
sorbitan trioleate (TWEEN 85).
In a particularly preferred embodiment form of
the invention one uses as component b) a combination con-
sisting of TWEEN 20, TWEEN 80 and TWEEN 60, or polysorbate
20, 80 and 60.
The component b) is contained in the pharma-
ceutical composition in a quantity part of approx. 1.0% to
5.0%, preferably 1.0% to 3.0% (with respect to the total
weight of
the formulation).
Component c) phospholipid of the formula I. The
nomenclature of the phospholipid (I) and the numbering of
the C-atoms is effected by way of the recommendations (sn-
nomenclature, stereospecific numbering) cited in the Eur.
J. of Biochem. 79, 11-21 (1977) of the IUPAC-IUB Commis-
sion on Biochemical Nomenclature (CBN).
Rl and R2 with the meanings Cl020-acyl are pre-
ferably straight chained Cl020-alkanoyl with an even number
of C-atoms and straight-chained Cl0_20 alkenoyl with a
double bonding and an even number of C-atoms.
~ CA 02238263 1998-0~-21
_ 10 --
Straight chained Cl0_20 alkanoyl R1 and R2 with
an even number of C-atoms are for example n-dodecanoyl, n-
tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.
Straight chained Cl0_20 alkanoyl Rl and R2 with a
double bonding and an even number of C-atoms are for
example 6-cis- or 6-trans-, 9-cis- or 9-trans-
dodecenoyl, -tetradecenoyl, -hexadecenoyl, -octadecenoyl
or -icosenoyl, in particular 9-cis-octadecenoyl (oleoyl),
further 9,12-cis-octadecadienoyl or 9, 12, 15-cis-octa-
decatrienoyl.
A phospholipid (I), wherein R3 indicates 2-tri-
methylamino-1-ethyl is described with the trivial name
lecithin and a phospholipid (I), wherein R3 indicates 2-
amino-1-ethyl is described with the trivial name kephalin.
Suitable for example are naturally occurring kephalin or
lecithin, e.g. kephalin or lecithin from soya beans or
chicken eggs with various or identical acyl groups Rl and
R2, or mixtures thereof.
The phospholipid ( I) may however also have a
synthetic origin. Under the term synthetic phospholipid
one defines phospholipids which with respect to Rl and R2
have a unitary composition. Such synthetic phospholipids
are preferably the lecithins and kephalins defined previ-
ously, whose acyl groups Rl and R2 have a defined struc-
ture and are derived from a defined fatty acid with a
CA 02238263 1998-0~-21
degree of purity of more than approx. 95%. Rl and R2 may
be the same or different and unsaturated or saturated.
Preferably Rl is saturated, e.g. n-hexadecanoyl, and R2
unsaturated, e.g. 9-cis-octadecenoyl (oleoyl).
The term "naturally occurring" phospholipid (I)
defines phospholipids which with respect to Rl and R2 do
not have a unitary composition. Such natural phospholipids
are likewise lecithins and kephalins whose acyl groups R
and R2 are structurally undefinable and are derived from
naturally occurring fatty acid mixtures.
The requirement "essentially pure" phospholipid
(I) defines a degree of purity of more than 90% (weight),
preferably more than 95%, of the phospholipid (I), which
can be proven by way of suitable methods of determination,
e.g. paper chromatographically, with thin film chromatog-
raphy, with HPLC or enzymatic colour test.
In a phospholipid (I) R3 has the meaning Cl4
alkyl for example methyl or ethyl. The meaning methyl is
preferred.
R3 with the meanings Cl_s-alkyl substituted by
carboxy, C25-alkyl substituted by hydroxy or C2_s-alkyl
substituted by carboxy or hydroxy are for example 2-
hydroxyethyl, 2,3-dihydroxy-n-propyl, carboxymethyl, 1- or
CA 02238263 1998-0~-21
2-carboxyethyl, dicarboxy-methyl, 2-carboxy-2-hydroxyethyl
or 3-carboxy-2,3-dihydroxy-n-propyl.
R3 with the meaning C25-alkyl substituted by
carboxy and amino is e.g. 3-amino-3-carboxy-n-propyl or 2-
amino-2-carboxy-n-propyl, preferably 2-amino-2-carboxy-
ethyl. Phospholipids (I) with these groups may be present
in salt form, e.g. as sodium or potassium salt.
Phospholipids (I), wherein R3 indicates the
inositol or glyceryl group, are known under the descrip-
tions phosphate idylinositol and polyphosphate idylgly-
cerol.
For the acyl residuals in the phospholipids (I)
as well as in the triglycerides (II) the descriptions
indicated in brackets are usual:
9-cis-dodecenol (lauroleoyl), 9-cis-tetradecenoyl (myrist-
oleoyl), 9-cis-hexadecenoyl (palmitoleoyl), 6-cis-octa-
decenoyl (petroseloyl), 6-trans-octadecenoyl (petrose-
laidoyl), 9-cis-octadecenoyl (oleoyl), 9-trans-octa-
decenoyl (elaidoyl), 9, 12-cis-octadecadienoyl
(linoleoyl), 9,12,15-cis-octadecatrienoyl (linolenoyl),
11-cis-octadecenoyl (vaccenoyl), 9-cis-icosenoyl
(gadoleoyl), 5,8,11,14-cis-eicosatetraenoyl (arachid-
onoyl), n-dodecanoyl (lauroyl), n-tetradecanoyl (myris-
toyl), n-hexadecanoyl (palmitoyl), n-octadecanoyl
CA 02238263 1998-0~-21
(stearoyl), n-icosanoyl (arachidoyl), n-docosanoyl
(behenoyl), n-tetracosanoyl (lignoceroyl).
A salt of the phospholipid (I) is preferably
pharmaceutically acceptable. Salts are defined by the exi-
stence of salt forming groups in substituents R3 as well
as by the free hydroxy group of phosphorous. Likewise the
formation of inner salts is also possible. Preferable are
alkali metal salts, in particular sodium salts.
The component c) is added in a preferred con-
centration of approx 0.05 to 1.0% by weight, preferably
0.05 to 0.1% by weight with respect to the total weight of
the formulation. In a particularly preferred embodiment
form one uses a purified lecithin of soya beans of the
quality LIPOID S 100.
Component d): in one of the triglycerides of
the formula II used as component d) R1, R2, R3 mean a
straight-chained C824-acyl with an even number of C-atoms,
in particular n-octanoyl, n-dodecanoyl, n-tetradecanoyl,
n-hexadecanoyl, n-octadecanoyl, 9-cis-dodecenoyl, 9-cis-
tetradecenoyl, 9-cis-hexadecenoyl, 9-cis-octadecenoyl or
9-cis-icosenoyl. The meanings of R1, R2, R3 maybe identical
or different, wherein the individual groups Rl, R2, R3
themselves are structurally unitarily defined. This is
characteristic for synthetic or semi-synthetic
triglycerides. Rl, R2, R3 may however also consist of vari-
CA 02238263 1998-0~-21
- 14 -
ous acyl groups of various structures. This is character-
istic for triglycerides of a natural origin.
A triglyceride of the formula II is a semi-syn-
thetic or synthetic, essentially pure triglyceride or apharmaceutically used triglyceride of a natural origin.
Preferred is a triglyceride of a natural originr e.g. pea-
nut oil, sesame oil, sunflower oil, olive oil, maize oil,
soya oil, castor oil, cotton seed oil, rape oil, thistle
oil, grape core oil, fish oil or coconut oil. In a par-
ticularly preferred embodiment form of the invention one
uses a triglyceride with the term neutral oil with various
acyl groups of a different structure, e.g. a triglyceride
of the fractioned coconut fatty acids C8-Cl0 of the type
Miglyol~, e.g. MIGLYOL 812.
The triglyceride (II) is, in the composition
defined further above, contained in a preferred concentra-
tion range of appro~. 0.1 to 2.0% by weight, preferably
0.1 to 1.0~ by weight with respect to the total weight of
the formulation.
The component e) - water as a carrier fluid in
the purity required for the dermal application, is accord-
ing to regulations of the national pharmaceutical list,free of germs and pyrogens.
CA 02238263 1998-0~-21
The component f) - aiding agents suitable for
dermal application is contained as a facultative com-
ponent. Such aiding agents are contained in creams, oint-
ments, gels, lotions, pastes, foams, tinctures or lotions.
Suitable are in particular ethanol, in particu-
lar in low quantity parts of approx 0.1 to 5%, isopropa-
nol, further preservatives, e.g. benzalconium chloride,
phenoxyethanol, further benzoe acids or their salts, 4-
hydroxy-benzoe acid esters (PHB-esters), phenols, e.g.
tert.-butyl-4-methoxy- or di-tert.-butyl-4-methylphenol,
benzylalcohol, 4-chlor- or 2,4-dichlorbenzylalcohol, 2-
phenylethanol, chlorhexidindi acetate or digluconate,
thiabendazol, cetyltriammonium bromide, cetylpyridinium
bromide, phenododecinium bromide or sorbic acid, antioxi-
dants, e.g. ascorbic acid, cysteine, sulphites, e.g.
sodium bisulphite, thioglycol or glutathion, essential
oils for improving the smell, i.e. menthol oil, orange
oil, bitter orange oil, mandarin oil or lemon oil, or sol-
vents or means for preventing evaporation, e.g. poly-
alcohols, e.g. propylene glycol, polyethylene glycol or
glycerine.
Likewise the subject-matter of the present
invention is the method, known per se, for manufacturing
the pharmaceutical composition, which is characterised in
that one mixes a lipophile phase consisting of the compo-
nents a) to d) with the aqueous carrier fluid which where
~ CA 02238263 1998-0~-21
~ .
- 16 -
appropriate contains aiding agents suitable for dermal
forms of administration, and where desired subjects the
obtainable clear opalescent dispersion based on nano-
particles - nanodispersion - to the following subsequent
operations: the addition of a further quantity of water as
a carrier fluid as well as where appropriate further water
soluble aiding agents, which are suitable for dermal forms
of administration, and where appropriate filtration (e.g.
sterile filtration) of the nanodispersion; and/or further
processing of the nanodispersion to a dermal preparation.
According to this method one manufactures a
lipophile phase ~oil phase" consisting of the component c)
- phospholipid (I) -, ethanol, component b) - partial
fatty acid ester of polyoxyethylene sorbitan -, component
a) - active ingredient, and of the component d) -
triglyceride (II). The mixing of the components is
effected at room temperature at low speed with a conven-
tional stirrer with a propeller or winged blade, a magnet
stirrer or static mixer.
In a preferred embodiment form of the invention
one uses a combination of various partial fatty acid
esters of polyoxyethylene sorbitan, in particular the com-
bination consisting of polysorbate 20, 80 and 60. At the
same time one respects the sequence, in that one first
mixes the phospholipid and the ethanol together and then
adds after one another polysorbate 20, 80, 60.
CA 02238263 1998-0~-21
Subsequently one adLds neutral oil. By mixing the lipophile
phase ("oil phasel') with the aqueous phase, which may con-
tain water soluble facultative additions, e.g. preserv-
atives, with a low speed mixing machinery (200 to 1,000
r.p.m.) there forms the pharmaceutical composition defined
earlier, which may be defined as a dispersion of colloidal
nanoparticles of the lipophile active ingredient
hydrocortisone or simplified as a nanodispersion. On
account of laser light dispersion measurements and record-
ings in the electron microscope the colloidal particles,present in the nanodispersion, of other formations such as
fluid crystals, micelles, reverse micelles or liposomes
may be distinguished. For the statistical majority of more
than 95~, preferably more than 98% an average particle
size of less than 50nm is characteristic.
For characterising the obtainable nanodispers-
ion, methods known per se are suitable, e.g. optical
judgement: weak to strong opalescence of the preparation
can be easily recognised (indication of an average
particle size of smaller than 50 nm), laser light disper-
sion (determining the particle size and homogeneity),
electron microscopy (freezing breakage and negative con-
trast technology).
The nanodispersion is after the addition of the
desired quantity of water and where appropriate further
aiding agents, applicable for dermal forms of administra-
CA 02238263 1998-0~-21
- 18 -
tion, e.g. directly applicable as a dosage spray. A par-
ticular advantage with respect to conventional dermal pre-
parations is the possibility of sterile filtration. If
desired by way of sterile filtration one may separate all
larger particles with a diameter larger than approx. 200
nm in the dispersion, as well as floating and solid mat-
ter, and thus manufacture a nanodispersion with a fraction
of particles with a relative uniform size.
Measured quantities of nanodispersion are
filled, where appropriate as a concentrate, in suitable
containers for a dose unit. Suitable vessels are e.g.
vessels for pump sprays or dosage sprays or plastic
vessels with an outlet device.
The pharmaceutical composition described
earlier with the anti-inflammatory agent hydrocortisone is
suitable as a dermal preparation for treating many dis-
eases of the skin or on the eye. At the same time one
applies the preparation in the prescribed dosage.
CA 02238263 1998-0~-21
- 19 -
The following example illustrates the
invention:
Recipe for a hydrocortisone 0.1% - nano-
5 colloidal dosage spray formulation.
position dosageamount component
%(w/w) g
1 0.0637.56 Lipoid S100
2 0.62575.00 Ethanol abs.
3 1.750210.00 Polysorbate 20
4 1.000120.00 Polysorbate 80
0.17521.00 Polysorbate 60
6 0.10512.60 hydrocortisone
Base micro BP88
7 0.75090.00 Miglyol 812
8 94.93011391.60 Aqua purificata
9 0.60272.24 phenoxyethanol
Total 100.0012000.00
By the addition of (9) into (8) at room temp-
erature one manufactures the aqueous phase. One obtains
the oil phase by placing (1) into (2) until the solution
becomes clear. Subsequently one adds after one another
(3), (4), and (5) - polysorbate 20, 80 and 60 and stirs,
until the mixture becomes clear. One adds the active in-
gredient (6) in three portions, and heats to 60~ C until
crystals are no longer visible. One adds (7) mixes until
the solution becomes clear and cools to room temperature
CA 02238263 1998-0~-21
- 20 -
One uni~ies the aqueous phase with the oil
phase, in that one places the aqueous phase at room tem-
perature and stirs at 300 - 400 r.p.m with a magnetic
stirring machinery. Subsequently one injects over a period
of time of approx. two minutes slowly under the level the
oil phase into the aqueous phase. One stirs for a further
5 - 10 minutes avoiding foam formation and filters the
nanodispersion through a germ filter (0.2~m).
