Stable emulsion suitable for pharmaceutical administration, the production thereof and emulsion for pharmaceutical use

A stable active substance emulsion of the oil-in-water type with a phospholipid as emulsifier is described, where the active substance dissolved in the lipid phase has one or more basic groups, is hydrophobic and oil-soluble, and has a pKa of at least 7.5, the aqueous phase is set at an acid pH, and the disperse phase gives a positive zeta potential of at least +15, but preferably +30, mV after dilution of the emulsion ready for administration to a fat content of 0.08% by weight.

The present invention relates to an emulsion of the oil-in-water type which 
contains a hydrophobic basic active substance dissolved in the oil phase. 
It is suitable for pharmaceutical, especially intravenous, administration 
and has very high stability which is based on an electrostatic repulsion 
of the disperse phase. 
DE-B 1 792 410 discloses that pharmaceutical compositions in which the 
active substance to be administered is finely dispersed or, in particular, 
dissolved in the hydrophobic phase of a system of the lipid-in-water type, 
are particularly well suited for intravenous administration and are often 
distinguished from aqueous presentations of the same active substance by 
being better tolerated and having fewer side effects. In many cases, an 
increase in activity has also been observed with these compositions. Used 
to stabilize the lipid-in-water system acting as carrier in this case are 
stabilizing substances of natural or synthetic origin such as 
phosphatides, polypropylene/polyethylene glycol, polyglycerol monooleate, 
and the amount thereof employed depends, according to the description, on 
the particular properties of the system. Used in the examples is a mixture 
of phosphatides, such as egg phosphatide, with nonionic emulsifiers, e.g. 
polyoxyethylene which is partially esterified with stearic acid, where 
1-2% by weight of phosphatide are employed together with about 0.5% by 
weight of the nonionic emulsifier in 10% oil-in-water emulsions. 
In contrast to the emulsions of DE-B 1 792 410 in which no organic solvents 
are used there are also proposals for the production of presentations for 
hydrophobic active substances in the form of fat emulsions in which 
organic solvents are employed as auxiliaries. Thus, U.S. Pat. No. 
4,784,845 proposes the use of benzyl alcohol as cosolvent for producing 
fat emulsions of, inter alia, those basic active substances whose pKa is 
below or near physiological pH, and which are therefore only very weakly 
basic, and DE-A 3 702 029 recommends the use of isopropanol for producing 
fat emulsions with, inter alia, 
2-dodecyl-5-(methyl-3-methoxyphenethylamino)-2-(3-methoxyphenyl)valeronitr 
ile (anipamil) as active substance by means of a complicated process, in 
which case this solvent is removed, at the same time as most of the water, 
from the system only after addition of a protective colloid such as 
gelatin. 
The resulting concentrate then contains only small amounts of water and is 
no longer a lipid-in-water emulsion within the meaning of the present 
invention. 
Such emulsions containing organic solvents are preferable to emulsions 
which comprise only an oil-in-water emulsion with a solvent-free aqueous 
phase and phospholipids as emulsifier, especially when they are 
administered intravenously, because the latter are similar to chylomicrons 
which carry out the physiological transport of fats in the blood and which 
contain phospholipids in the membrane (see DE-B 1 792 410). They are 
therefore more acceptable from the physiological standpoint. 
It is likewise emphasized by Davis, S. S. et al., Ann. New York Acad. Sci. 
507 (1987) 76-79, who point out therein the importance which has been 
acquired by emulsions of the oil-in-water type as form for the 
administration of oil-soluble but not water-soluble pharmaceutical active 
substances, that such emulsions, which are usually composed of 10-20% by 
volume of a vegetable oil which is stabilized by 1-2% by weight of 
phosphatides, are similar to chylomicrons and are superior to systems 
based on organic solvents and synthetic surfactants such as Cremophor, 
because their intravenous tolerability is better. 
These emulsions also have a certain similarity to liposomes, but differ 
from the latter, according to Davis, S. S. et al., by being more easily 
produced in a well-tested manner and having good storage stability. It is 
an advantage that such fat emulsions can also be used as presentation for 
those active substances which are unstable in aqueous medium or show 
undesired side effects in aqueous presentations. On the other hand, it is 
regarded as a disadvantage that some active substances crucially impair 
the stability of the basic emulsion or even destroy the emulsion. No 
reason for the adverse effect of some active substances is given. 
S. S. Davis has also pointed out, in Adv. Clin. Nutrition--Proc. 2nd Int. 
Symp. Editio I. D. A. Johnston 1982, pages 213-239, that the stabilizing 
effect of emulsifiers can be both mechanical and electrical in nature, the 
mechanical stabilization being based on the formation of a thick film at 
the interface, and the electrical stabilization being based on an 
electrostatic repulsion of the droplets of the disperse phase by a charge 
of the same type at the interface. Employed for parenteral administration 
are primarily fat emulsions with lecithin of animal or vegetable origin as 
emulsifier, which, because of additions of small amounts of acid such as 
phosphatidic acid, phosphatidylserine and similar substances, confer on 
the fat droplets a negative charge which is crucial for the stability of 
such emulsions. These electrostatic forces may be expressed by the zeta 
potential of the fat droplets which is, according to Ro/ mpps Chemie 
Lexikon, Otto Albrecht Neumu/ ller--Stuttgart: Franckh, Vol. 6, 8th 
edition, page 4695, the potential of the particles which acts outwards and 
is responsible for their electrokinetic phenomena and is therefore also 
called electrokinetic potential. The stability of the emulsion increases 
with the size of the negative zeta potential. 
Davis also points out that addition of cations reduces the negative zeta 
potential of the fat emulsions, which is at from -40 to -50 mV in 
commercial fat emulsions, and thus leads to instability of the emulsion. 
In the case of singly charged cations such as sodium or potassium ions, 
addition of more than 130 mmol/l destroys the emulsion, and in the case of 
doubly or triply charged cations the destructive effect occurs at 
considerably lower concentrations. Addition of multiply charged cations 
may even result in complete discharge of the fat droplets or a change in 
charge to a positive zeta potential. 
The present invention is based on the finding that it is usually basic 
active substances which cause the instability of fat emulsions intended to 
act as carriers for these active substances. This destabilizing effect 
increases with the pKa of the basic active substance. Thus, it is true 
that it is possible to produce stable pharmaceutical compositions based on 
fat emulsions with weakly basic active substances, such as diazepam, or 
weakly acid active substances, such as propofol, and it has emerged that 
this is connected with there being little or no change owing to the 
addition of the said active substances in the negative zeta potential of 
the fat emulsion forming the basis. On the other hand, it has been found, 
surprisingly, that with more strongly basic active substances, especially 
those with a pKa of 8 or above, the positive ionization of the active 
substance at pH 7 may, despite its insolubility in water, suffice in a 10% 
strength soybean oil emulsion virtually to neutralize the negative charge 
at the interface of the fat droplets or even to bring about a certain 
change in charge and thus eliminate the electrostatic repulsion which has 
a stabilizing effect. Thus, for example, in the case of the known calcium 
antagonist 
(-)-(S)-2-isopropyl-5-(methylphenethylamino)-2-phenylvaleronitrile 
(levemopamil), which is extremely hydrophobic [partition coefficient 
(octanol/water, non-ionized) log P 6-7, determined by calculation] and has 
a pKa of 8.58, it has emerged that the ionized proportion of 2% in an 
emulsion containing 10% soybean oil suffices to change the zeta potential 
of the emulsion, which is -40 mV with no active substance present, to -10 
to +5 mV at pH 7, which is the reason for the instability of the 
pharmaceutical composition with this active substance. 
We have now found, surprisingly, that hydrophobic, strongly basic active 
substances can be formulated to stable pharmaceutical compositions based 
on an oil-in-water emulsion stabilized with phospholipid when an acidic pH 
which is sufficient to bring about a change in charge to a highly positive 
zeta potential is set up in the aqueous phase by addition of a buffer 
system. The setting up of an acid pH in the aqueous phase, for example to 
pH 6 or below, increases the ionization of the active substance which is 
sparingly soluble in water to such an extent that the zeta potential of 
the disperse phase is shifted, while maintaining the solubility in oil, so 
far into the positive range that the repulsive forces of the now 
positively charged fat droplets suffice to stabilize the emulsion. This is 
surprising because this effect occurs even at relatively low 
concentrations of active substance based on the complete system. Thus, for 
example, in the case of levemopamil 2% of active substance, based on the 
complete system, which is 60 mmol/l, of which only a fraction is ionized, 
suffices to give a positive zeta potential of about +35 to +40 mV at pH 
6. The zeta potential can even be increased to above +50 mV by setting up 
a pH of 5. 
Naturally, the electrostatic conditions in the emulsion ready for 
administration are crucial for the occurrence of the stabilizing effect. 
However, it has emerged in practice that it is not possible to measure the 
zeta potential, for example by measurement of the rate of migration by 
microelectrophoresis, coupled with a laser Doppler velocimetry, in these 
emulsions which contain 5-30% by weight fat, because the transparency of 
these emulsions is too low. On the other hand, there is in the present 
case the difficulty that the positive zeta potential resulting in the 
finished composition is not attributable to the presence of foreign 
electrolytes in the aqueous phase, on the contrary these electrolytes are 
formed by the active substance which is present in the oil phase 
undergoing ionization, which is increased by dilution of the sample. The 
effect of the dilution necessary for measurement is so serious in this 
connection that, as our investigations have shown, emulsions whose zeta 
potential is approximately in the range from +40 to +60 mV reach the zero 
point or even slip into negative values with dilutions of from 1:4,000 to 
1:10,000. However, it has emerged that zeta potentials can be measured at 
fat concentrations of 0.08% by weight using commercial laser 
electrophoresis and submicron particle size distribution analyzers, and 
the results correlate very well with those of the undiluted emulsion, as 
is evident from the dilution plot. In this connection, see FIG. 1, change 
in zeta potentials of dilutions containing from 0.08% by weight to 0.0002 
% by weight of oil. If measurement of a 0.08% by weight emulsion reveals a 
positive zeta potential of at least +15 mV, it has emerged that the stable 
range for this emulsion has been reached, and it is advisable to prepare 
emulsions which, on measurement of the composition ready for 
administration which has been diluted to a fat content of 0.08% by weight, 
have a zeta potential of at least +30 mV, preferably of at least +40 mV, 
to ensure long-term stability and autoclavability at 120.degree. C. 
These emulsions containing 0.08% by weight fat are obtained, for example, 
when an originally 
20% by weight fat emulsion is diluted 250 fold, 
10% by weight fat emulsion is diluted 125 fold and 
5% by weight fat emulsion is diluted 62.5 fold. 
Thus, all the positive zeta potentials stated in the following description 
were deter-mined on emulsions containing 0.08% by weight fat. 
Accordingly, the present invention relates to stable emulsions which are 
suitable for pharmaceutical, especially intravenous, administration of the 
oil-in-water type with a fat content of 5-30 % by weight and a content of 
0.5-2% by weight of a phospholipid as emulsifier, and which contain in the 
lipid phase a hydrophobic pharmaceutical active substance carrying one or 
more basic groups in finely dispersed and/or dissolved form, wherein the 
active substance is soluble in oil and has a pKa of at least 7.5, the 
aqueous phase is set at an acid pH by containing a physiologically 
tolerated buffer system, and the disperse phase gives a positive zeta 
potential of at least +15 mV after dilution of the emulsion ready for 
administration to a fat content of 0.08% by weight. 
The level of the positive zeta potential of the emulsion ready for 
administration is responsible for the stability of the emulsion, because 
only after a minimum positive charge has been reached on the interface are 
the repulsive forces so large that creaming or oil formation is prevented. 
The exact pH which must be set up in the aqueous phase in order to exceed 
the required limit of +15 mV depends not only on the basicity of the 
active substance, expressed by its pKa, but also to a certain extent on 
the concentration of the active substance in the composition, i.e. the 
higher the concentration, the lower the acidity required to reach the 
required positive charge in the disperse phase. Finally, the lecithin is 
also included, since the negative zeta potentials of lecithins can vary, 
depending on the purity, from -40 or -50 mV to near 0 (in the case of pure 
phosphatidylcholine), measured on a fat emulsion containing no active 
substance at pH 7.4. 
Finally, the ion concentration which results in the aqueous phase by the 
interaction of all these factors is crucial while maintaining the 
solubility of the active substance in oil. In this connection it may be 
assumed that the value of +15 mV is the lower limit for stability of the 
composition. 
A positive zeta potential of at least +30 mV is preferred, and one of at 
least +40 mV is particularly preferred, especially when the composition is 
to be autoclaved. 
Besides the solubility in oil, it is also important that the hydrophobicity 
of the active substance is maximal, and it is necessarily true here too 
that a high hydrophobicity favors the formation of a high positive zeta 
potential but, at the same time, ensures that most of the active substance 
remains in the oil phase. It may be assumed that the hydrophobicity is 
high at a partition coefficient log P, measured in the octanol/water 
system, non-ionized, which is considerably higher than 2.5-3, the limit of 
2.5-3 resulting from the detection limit for many active substances. 
Calculated values of log P should preferably exceed 4. 
For a chosen active substance, it is advisable to determine by a 
preliminary test the pH at which a sufficiently high positive zeta 
potential is set up. It has emerged in practice that sufficiently high 
positive zeta potentials to obtain emulsions with excellent stability are 
usually achieved at pH values in the range 4-5.5, especially when the 
chosen active substance has a pKa of at least 8. 
The chosen pH for strongly hydrophobic active substances with a pKa of 8-10 
and an active substance content of 0.5-3% by weight is particularly 
preferably in the range 4-5.5, in which case the emulsion should contain 
8-25% by weight of a vegetable oil and 1-2% by weight of a phospholipid as 
emulsifier. 
A considerable reduction in the pH beyond that necessary to achieve the 
required zeta potential is not worthwhile and entails the risk of reducing 
the solubility of the base in oil too far. This may lead to reduced 
tolerability of the composition. As a rule, the acidity +should not be 
increased further after a zeta potential of 60 mV has been reached. 
The required pH can be set up by using all buffer systems which are 
approved for pharmaceuticals for intravenous administration and which do 
not react with the active substance. Examples of such buffer systems are 
acetate/acetic acid buffer, phosphate buffer and citrate buffer. The fat 
component can be any conventional fat, especially oil, used for preparing 
fat emulsions intended for i.v. administration. Vegetable oils, such as 
soybean, peanut, safflower, olive, corn, rapeseed, coconut, sesame, 
sunflower, palm oil and the like, are preferred. The fat content is 5-30% 
by weight, expediently 8-25% by weight, preferably 10-20% by weight. It is 
advantageous to increase the fat content as the active substance content 
increases. 
Phospholipids which may be mentioned are both the conventional egg 
phosphatides and soybean phosphatides, it being possible to use both those 
containing about 80% phosphatidylcholine and a certain proportion of acid 
impurities, which results in a negative zeta potential of -40 to -50 mV in 
a fat emulsion containing no active substance at pH 7.4, and more highly 
purified products which are 90% or more composed of one or more 
phosphatidylcholines. It is also possible to employ pure 
phosphatidylcholines which carry scarcely any negative charge. It is 
easiest using these to achieve high positive charges in the disperse 
phase. The nature of the chosen phospholipid must, as already mentioned, 
also be taken into account in the choice of the pH. Surprisingly, the 
effect of relatively large amounts of acid constituents in the emulsifier 
is considerably less at the acid pH values to be set up according to the 
invention than at neutral pH, so that even with conventional phospholipids 
which yield emulsions with a negative zeta potential of -40 to -50 mV 
without an active substance content at pH 7.4, it is possible usually to 
achieve sufficiently high positive zeta potentials, even exceeding +30 mV, 
at pH values below 6. The amount of phospholipid is expediently from 1 to 
2% by weight. It is also possible, if desired, to use other conventional, 
especially non-ionic, emulsifiers together with the phospholipid. 
Basic hydrophobic active substances which are suitable for producing the 
stable emulsions according to the invention are all those which, besides 
basicity, have pronounced hydrophobicity and are soluble in oil. Very 
favorable results are obtained with active substances belonging to the 
group of 5-(phenethylamino)-2-phenylvaleronitriles, with levemopamil being 
particular preferred. This active substance can be converted according to 
the invention into very stable and extremely well tolerated presentations 
based on a fat emulsion as carrier. These have no unpleasant side effects 
whatever on administration and, in this respect, are superior to aqueous 
presentations of this active substance. Very good results are also 
achieved with 
2-dodecyl-5-(methyl-3-methoxyphenethylamino)-2-(3-methoxyphenyl)valeronitr 
ile (anipamil). Very good results are also achieved with active substances 
belonging to the group of neuroleptic phenothiazines with basic groups, 
particular attention being drawn to 
10-(3-dimethylaminopropyl)phenothiazine with pKa 9.4 (promazine), 
10-(2-dimethylaminopropyl)phenothiazine, pKa 9.1 (promethazine) and 
4-{3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl}-1-piperazinoethanol, 
pKa 8.05 (fluphenazine). Finally, it is also possible to convert basic 
local anesthetics, such as tetracaine, into presentations according to the 
invention. 
To produce the emulsions according to the invention, the oil, the active 
substance and the emulsifier are mixed into the aqueous phase which has 
already been set at the pH which is required, or has been determined by 
the preliminary test, by the buffer system. Preliminary emulsification of 
the mixture is followed by final treatment by multiple high-pressure 
homogenization which is continued until an average particle size of below 
500 mm is reached. It is possible for the active substance first to be 
dissolved in the oil, after which the resulting mixture is introduced into 
a previously dispersed mixture of the phospholipid with the aqueous phase 
containing the buffer. 
However, it is equally possible first to mix the active substance with the 
phospholipid, to disperse this mixture in the aqueous phase and 
subsequently to mix in the oil. It is possible to use conventional 
high-pressure homogenizers or microfluidizers for the high-pressure 
homogenization. 
It is desirable in many cases to adjust the osmotic pressure to 
physiological conditions, especially when the emulsion according to the 
invention is to be administered intravenously. This adjustment can be 
carried out by adding a physiological non-ionic substance. Glycerol is 
preferred in this connection. 
The zeta potential was determined in the following examples using a 
commercial apparatus (Zetasizer 3 supplied by Malvern), in which the 
microelectrophoresis is coupled to photon correlation spectroscopy based 
on a helium/neon laser. The evaluation was carried out by an on-line 
computer. 
The drawing shows the change in the zeta potentials taking the example of 
levemopamil at various dilutions from 0.8 to 0.002 g/l or 0.08 to 0.0002% 
by weight of fat, which correspond to dilutions of from 1:250 to 1:10,000 
starting from a 20% strength fat emulsion. The starting emulsions had 
various fat contents and/or active substance contents and were set at pH 
5. 
The plots are based on the following figures: 
______________________________________ 
Active 
substance Zeta potentials in mV at g/l fat 
Fat content 
content 0.8 0.4 0.2 0.02 0.002 
______________________________________ 
20% 2% 55.8 49.0 41.9 -4.9 -6.3 
10% 2% 53.1 45.1 35.7 -17.2 -5.7 
10% 1% 57.1 49.2 42.5 -9.2 -6.6 
5% 2% 53.2 48.1 41.9 -11.8 -1.8 
5% 1% 51.6 42.6 34.1 -14.5 -3.5 
20% 0.5% 35.1 32.0 19.0 -2.1 -6.3 
______________________________________ 
The low gradients obtained from 0.8 to 0.2 g/l fat underline the relevance 
of the values for the zeta potential found at 0.8 g/l fat or 0.08% by 
weight for the electrostatic conditions in the undiluted emulsion. 
The emulsions according to the invention can be employed for all purposes 
for which liquid presentations of pharmaceutical active substances are 
used. They are particularly suitable for oral, nasal, pulmonary or vaginal 
administration. A particular advantage is that they are, by reason of 
their composition, not merely suitable for intravenous administration but 
in fact especially suited to this, and are very well tolerated.

EXAMPLE 1 
12 g of OVOTHIN.RTM. 200 suitable for parenteral administration, which is 
more than 90% composed of phosphatidylcholine and gives a zeta potential 
of -20 mV as a fat emulsion without active substance in water at pH 7.4, 
were suspended in 725 ml of an acetate/acetic acid buffer solution (5 
mmol/l), which had been set at pH 5, at 50.degree.-60.degree. C. and mixed 
with 23 g of 86% pure glycerol to adjust the osmotic pressure. The 
resulting aqueous mixture was then prehomogenized once under 200 bar. 20 g 
of levemopamil were dissolved, likewise at 50.degree.-60.degree. C., in 
200 g of soybean oil; the resulting oil phase was dispersed in portions in 
the aqueous phase and emulsified once under 200 bar. After the pH had been 
readjusted to 5 by adding acetic acid, the complete mixture was 
homogenized 3 times under 200 bar. If larger particles were still 
detectable after this, these were reduced in size by a subsequent 
emulsification. 
The resulting emulsion was left to cool to room temperature under a 
nitrogen atmosphere, filtered through a 5 .mu. filter and bottled. 
Sterilization at 121.degree. C. for 15 minutes resulted in an emulsion 
with the following characteristics: zeta potential of a 250-fold dilution 
corresponding to a fat concentration of 0.08% +56 mV, average particle 
size 255 nm, active substance content 2 g/100 ml, which is 60 mmol/l. 
Emulsions of pH 4 and pH 6 were produced in a similar manner. 
Characteristics at pH 4: zeta potential+54 mV, particle size 210 nm, active 
substance concentration 2% 
Characteristics at pH 6: zeta potential+37 mV, particle size 300 nm, active 
substance concentration 2% 
EXAMPLE 2 
20 g of anipamil in the form of the free base were mixed with 200 g of 
soybean oil. 12 g of OVOTHIN.RTM. 200 were dispersed as described in 
Example 1 with 725 ml of a sodium acetate/acetic acid buffer solution set 
at pH 5, mixed with the oil/active substance mixture and subjected to the 
high-pressure homogenization. 
Sterilization in a rotary autoclave at 121.degree. C. for 15 minutes 
resulted in an emulsion with the following values: 
zeta potential +54 mV, average particle size 300 nm, active substance 
content 2 g/100 ml, which is 60 mmol/l. Anipamil-containing emulsions with 
2% active substance in 20% fat with pH values of 4 and 6 were obtained in 
an entirely corresponding manner. 
The characteristics of these were as follows: 
pH 4: average particle size 270 nm, zeta potential +56 mV, active substance 
content 2 g/100 ml 
pH 6: average particle size 330 nm, zeta potential +41 mV, active substance 
content 2 g/100 ml 
EXAMPLE 3 
12 g of OVOTHIN.RTM. in 200 were suspended at 50.degree.-60.degree. C. in 
825 ml of an aqueous sodium acetate/acetic acid buffer solution (5 mmol/l) 
set at pH 5 and subsequently 20 g of glycerol and then 20 g of levemopamil 
base were stirred in, after which the pH was returned to 5 by adding 
acetic acid. After prehomogenization, 100 g of soybean oil were introduced 
in portions and dispersed, after which the mixture was subjected to a 
high-pressure homogenization 3 times under 200 bar. Any larger particles 
still present were converted into smaller particles by subsequent 
homogenization. After cooling, the emulsion was autoclaved at 121.degree. 
C. It then had the following characteristics: 
zeta potential +53 mV, average particle size 230 nm, active substance 
content 2 g/100 ml, which is 60 mmol/l, fat content 10% by weight. 
EXAMPLE 4 
12 g of an egg lecithin containing 90% phosphatidylcholine, which gave a 
zeta potential of -20 mV at pH 7.4, (OVOTHIN.RTM. 200) and 20 g of 
glycerol were dispersed in 875 ml of a sodium acetate/acetic acid buffer 
solution set at pH 5 as described in Example 1, and, at 
50.degree.-60.degree. C., a mixture of 20 g of levemopamil base and 50 g 
of soybean oil was added in portions. The mixture was homogenized first 
under 200 bar and, after correction of the pH, the homogenization was 
continued under 140 bar until the average particle size was 220 mm. After 
the bottling and sterilization carried out as in Example 1, the emulsion 
gave a zeta potential of +53 mV. The average particle size was 220 mm. The 
active substance content was 2 g/100 ml, which is 60 mmol/l, and the fat 
content was 5% by weight. 
EXAMPLE 5 
1 g of levemopamil base was mixed with 5 g of soybean oil. The mixture was 
added to a previously dispersed mixture of 1.2 g of a highly purified 
lecithin, 2 g of glycerol and 88 ml of a buffer solution set at pH 5, and 
was subjected to high-pressure homogenization with the pressure increasing 
from 140 to 200 bar. Sterilization in a rotary autoclave at 121.degree. C. 
for 15 minutes resulted in an emulsion with the following values: zeta 
potential +52 mV, average particle size 230 nm, active substance content 1 
g/100 ml corresponding to 30 mmol/l, fat content 5% by weight. 
EXAMPLE 6 
12 g of egg lecithin with a zeta potential of -20 mV were dispersed 
(Ultraturrax) in 730 ml of an acetic acid/acetate buffer solution (5 
mmol/l) of pH 5 isotonisized with glycerol; 20 g of promethazine base were 
incorporated in this dispersion and then the resulting mixture was mixed 
with 200 g of soybean oil and emulsified 4 times in a high-pressure 
homogenizer under 200 bar. After 15 minutes in a rotary autoclave at 
121.degree. C., the emulsion had the following characteristics: 
zeta potential +46 mV, average particle size 250 nm, active substance 
content 20 g/l, fat content 20% by weight. 
Promethazine-containing emulsions of pH 4 and pH 6 were prepared in a 
corresponding manner. 
Characteristics at pH 4: zeta potential +52 mV, average particle size 250 
nm, active substance content 20 g/l 
Characteristics at pH 6: zeta potential +41 mV, average particle size 280 
nm, active substance content 20 g/l 
EXAMPLE 7 
2 g of promazine base were dispersed as described in Example 6 in 73 ml of 
buffer/glycerol solution of pH 5 which contained 1.2 g of the same egg 
lecithin as used in Example 6 with 20 g of soybean oil, and then subjected 
to high-pressure homogenization 4 times with the pressure increasing each 
time from 140 to 200 bar. After autoclaving a stable emulsion With the 
following characteristics was obtained: zeta potential +44 mV, average 
particle size 230 nm, active substance content 2%, fat content 20% by 
weight. The emulsions with pH 4 and pH 6 produced correspondingly had zeta 
potentials of +56 mV (pH 4) and +39 mV (pH 6) with the other 
characteristics the same. 
EXAMPLE 8 
10 g of levemopamil were dissolved in 100 g of soybean oil to prepare an 
emulsion. This mixture was dispersed with a high-speed stirrer at about 
60.degree. C. in 825 ml of an acetate buffer solution which was set at pH 
5 and isotonisized with glycerol and which contained 12 g of OVOTHIN.RTM. 
200, and was subjected to high-pressure homogenization in 4 steps under 
200 bar. 
Bottling and sterilization in a rotary autoclave at 121.degree. C. for 15 
min. resulted in an emulsion with the following characteristics: 
zeta potential +57 mV, average particle size 300 nm, active substance 
content 10 g/l corresponding to 30 mmol/l, fat content 10% by weight. 
EXAMPLE 9 
20 g of levemopamil dissolved in 200 g of soybean oil were incorporated 
using a high-speed stirrer into 725 ml of an acetate buffer solution which 
was isotonisized with glycerol and set at pH 5 and which contained 12 g of 
an egg lecithin with a phosphatidylcholine content of 80% and a zeta 
potential at pH 7.4 of -40 to -50 mV (LYPOID E 80.RTM.), and subsequently 
subjected to high-pressure homogenization in 4 steps under 160-180 bar. 
The emulsion produced in this way was filtered through 5.mu. filters, 
bottled and sterilized at 121.degree. C. with rotation for 15 min. The 
following values were measured on the finished emulsion: 
zeta potential +44 mV, average particle size 300 nm, active substance 
content 20 g/l, fat content 20% by weight.