PROCEDE DE PRODUCTION DE COMPOSES PHARMACEUTIQUES CONTENANT DES LIPOSOMES UNILAMELLAIRES

PROCESS FOR THE MANUFACTURE OF PHARMACEUTICAL COMPOSITIONS CONTAINING UNILAMELLAR LIPOSOMES

Abrégé anglais

Abstract
Process for the manufacture of pharmaceutical compositions
containing unilamellar liposomes
The present invention relates to a process for the
maunfacture of pharmaceutical compositions in the form
of aqueous dispersions containing unilammellar liposomes
comprising (I) an amphiphatic compound having biological
activity and (II) a phospholipid or an analogous lipid and,
optionally, an additional lipid. The liposome dispersion is
obtained by preparing a homogenous mixture of the components
and by dispersing the homogenous mixture in an aqueous phase.
The unilamellar liposomes can be used therapeutically as
carriers of amphiphatic pharmaceuticals of extremely varied
kinds.

Revendications

- 55 -
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the manufacture of pharmaceutical
compositions in the form of aqueous dispersions containing
unilamellar liposomes comprising (I) an amphiphatic compound
having biological activity and (II) a phospholipid or an
analogous lipid and, optionally, an additional lipid,
characterized in that (I) the amphiphatic compound having
biological activity and (II) the phospholipid or the analog-
ous lipid and, optionally, the additional lipid are homo-
geneously mixed and the resulting homogeneous mixture is
dispersed in an aqueous phase and the resulting aqueous
dispersion is neutralised.
2. Process according to claim 1, characterised in that
there are homogeneously mixed and dispersed (I), as the
amphiphatic compound having biological activity,
a substituted ammonium compound of the formula
<IMG> (1)
in which
a) Ra represents a hydrophobic group, and Rb, Rc and Rd,
independently of one another, each represents hydrogen,
C1-C4-alkyl, 2-hydroxyethyl, allyl or cyclo-C3-C6-alkyl-
C1-C3-alkyl, or two of the radicals Rb, Rc and Rd together
represent C4- or C5- alkylene or such group interrupted by
-HN-, -N(C1-C4-

- 56 -
alkyl)-, -N(2-hydroxyethyl)- or by oxygen, or
b) Ra and Rb are two hydrophobic groups or
together represent a hydrophobic group, and Rc and
Rd, independently of one another, each represents
hydrogen, C1-C4-alkyl, allyl or cyclo-C3-C5-alkyl-
C1-C3-alkyl, or
c) Ra, Rb and Rc together represent a hydro-
phobic group, and Rd represents hydrogen or
C1-C4-alkyl, and X? represents the anion of a
pharmaceutically acceptable acid,
a carboxylic acid salt of the formula
Ra-COO ? Y ? (2)
in which Ra represents a hydrophobic group, and Y?
represents the cation of a pharmaceutically acceptable
base,
an .alpha.-amino acid compound of the formula
<IMG> (3)
in which Ra represents a hydrophobic group, and Rb
and Rc, independently of one another, each represents
hydrogen or C1-C4-alkyl.
a phosphoric acid monoester of the formula

- 57 -
<IMG> (4)
in which Ra represents a hydrophobic group and Y
represents the cation of a pharmaceutically acceptable
base, or
an acid addition salt of a compound having a hydro-
phobic group Ra and an imidazoline, imidazolidine or
hydrazino group as hydrophilic group, and (II), as the
phospholipid, a compound of the formula
(5)
<IMG>
in which one of the radicals R1 and R2 represents
hydrogen, hydroxy or C1-C4-alkyl, and the other
radical represents alkyl, alkenyl, alkoxy, alkenyloxy or
acyloxy each having from 10 to 20 carbon atoms, or
both radicals R1 and R2 represent alkyl, alkenyl,
alkoxy, alkenyloxy or acyloxy each having from 10 to 20
carbon atoms, R3 represents hydrogen or C1-C4-
alkyl, and R4 represents hydrogen, C1-C7-alkyl,
substituted C1-C7-alkyl or a carbohydrate radical
having from 5 to 12 carbon atoms or, if both radicals

- 58 -
R1 and R2 represent hydrogen or hydroxy, R4 represents
a steroid radical, or is a salt thereof.
3. Process according to claim 2, characterised in that
there are homogeneously mixed and dispersed (I) a substi-
tuted ammonium compound of the formula 1 in which
a) the hydrophobic group can be an aliphatic
hydrocarbon radical that can be interrupted by an
oxygen or sulphur atom, may contain the groups -CO(=O)-,
-O-C(=O)-, -C(=O)-NH-, -O-C(=O)-NH- or hydroxy, and
can be substituted by from 1 to 3 monocyclic, aliphatic
or aromatic hydrocarbon radicals, by a bi- or tri-cyclic,
aromatic or partially saturated hydrocarbon radical, by a
monocyclic, aromatic, partially saturated or saturated
heterocycle or by a bi- or tri-cyclic, aromatic, partially
saturated or benzo-fused heterocycle, or can be a mono-
cyclic, aliphatic or aromatic hydrocarbon radical or a
bicyclic, aliphatic or benzo-fused hydrocarbon radical,
and the hydrophilic group is a group of the formula
<IMG>

in which Rb, Rc and Rd, independently of one another,
each represents hydrogen, C1-C4-alkyl or 2-hydroxyethyl,
or in which two of the radicals Rb, Rc and Rd together
represent piperidino, piperazinyl, 1-methylpiperazinyl,
1-(2-hydroxyethyl)-piperazinyl or morpholino, and the
other radical represents hydrogen, or
b) the hydrophobic groups Ra and Rb can be two aliphatic
hydrocarbon radicals which can be substituted by one or two
monocyclic, aliphatic or aromatic hydrocarbon radicals or
by substituted, monocyclic, aromatic, partially saturated
or saturated heterocycle, or Ra and Rb together represent a
monocyclic, aromatic, saturated, partially saturated or
benzo-fused heterocycle, and the hydrophilic group is a
group of the formula
<IMG>
in which Rc and Rd, independently of one another, each
represents hydrogen or C1-D4-alkyl, or
c) the hydrophobic group is formed by Ra, Rb and Rc
together and represents an aromatic, partially saturated or
benzo-fused heterocycle and the hydrophilic group is a group
of the formula
<IMG>

- 60 -
in which Rd represents hydrogen or C1-C4-alkyl, and
X is the anion of a pharmaceutically acceptable acid, or
a carboxylic acid salt of the formula 2 in which the hydro-
phobic group Ra can be an aliphatic hydrocarbon radical
which can be substituted by a monocyclic, aromatic hydro-
carbon radical or by a bi- or tri-cyclic, aromatic or
partially saturated hydrocarbon radical, by a monocyclic,
aromatic or partially saturated heterocycle or by a bi- or
tri-cyclic, aromatic, partially saturated or benzo-fused
heterocycle or by a steroid radical, or Ra can be a mono-
cyclic, aromatic hydrocarbon radical, a bi- or tri-cyclic,
aromatic or partially saturated hydrocarbon radical, a
monocyclic, aromatic or partially saturated heterocycle or
a bi- or tri-cyclic, aromatic, partially saturated or
benzo-fused heterocycle, and Y? is the cation of a
pharmaceutically acceptable base, and (II), as the phospho-
lipid, a compound of the formula 5 in which both radicals
R1 and R2 represent alkyl, alkenyl, alkoxy, alkenyloxy or
acyloxy each having from 10 to 20 carbon atoms, R3
represents hydrogen or C1-C4- alkyl, and R4 represents
hydrogen or C1-C4-alkyl, and R4 represents hydrogen, C1-C7-
alkyl or substituted C1-C7-alkyl or a carbohydrate radical
having from 5 to 12 carbon atoms, or a salt thereof.
4. Process according to claim 2,
characterised in that there are homogeneously mixed and
dispersed (I), as the substituted ammonium compound or as
the corresponding amino compound that can be converted into
the ammonium compound by salt formation,

- 61 -
a compound selected from the group comprising
parasympathomimetics having quaternary or tertiary
amino groups, choline esterase inhibitors having two
tertiary amino groups or having a quaternary ammonium
group, neurotransmitters having a quaternary ammonium
group, serotonin-antagonists in which the hydrophilic
group is a primary or tertiary amino group and the
hydrophobic group has an indol-3-ylethyl structure,
analgesics of the morphine type having a tertiary amino
group and their antagonists of the formula
<IMG> (1.1)
in which R1, R2 and R3 have the following
meanings:
<IMG>

- 62 -
<IMG>
analgesics of the benzomorphan type having a tertiary
amino group, analgesics of the pethidine type,
analgesics of the methadone type in which the hydrophobic
group is a 1,1-diphenyl-1-lower alkyl-2-butanone radical
and the hydrophilic group is dimethylamino, morpholino or
piperidino of the formula
<IMG> (1.2)
in which R1 represents hydrogen or methyl, R2 and R3 each
represents methyl, or R2 and R3 together represent
morpholino or piperidino, or analogues thereof having
a pseudomethadone structure, analgesics

- 63 -
similar to morphine having an aliphatic or cycloaliphatic
tertiary amino group, analgesics of the benzimidazole type
of the formula
<IMG>
(1. 3)
in which R1 represents 5-, 6- or 7-nitro, R2 represents
hydrogen, 3 '- or 4'-methoxy, 4'-ethoxy, 4'-isopropoxy, 4'-
methyl or 4'-chloro, local anaesthetics in which Ra and Rb
in the formula 1 together with the nitrogen atom form a
piperidyl radical that is substituted by a 1,3-propylene,
that is itself substituted by a methoxycarbonyl and benzoyl-
oxy group, local anaesthetics in which the hydrophobic
group Ra in the formula (1) is a 4-aminobenzoyloxyethyl,
4-amino-2-chloro-, 2-n-butoxy- or 2-hydroxy-benzoyloxyethyl,
4-amino-3-n-butoxybenzoyloxyethyl, 3-amino-4-n-butoxy-
benzoyloxyethyl, 2-aminobenzoyloxyethyl, 2-(4-aminobenz-
oyloxy)-6-methyl-n-pentyl, 4-aminobenzoyloxy-n-propyl,
4-n-butylaminobenzoyloxyethyl, 4-n-butyl-2-hydroxybenz-
oyloxyethyl, 3-(4-n-propoxybenzoyloxy-2-hydroxy)-propyl,
2-n-benzoyloxy-n-propyl, 2-(2-acetoxybenzoyloxy)-n-propyl,
benzoyloxy-n-propyl, 4-cyclohexyloxybenzoyloxyethyl, 4
ethyl- or 4-n-butyl-benzoyloxyethyl, 2-n-butoxyquinol-4-
ylcarbonyloxyethyl, 2,4-dimethylanilinocarbonylmethyl, 2-
ethyl-, 2-chloro-

- 64 -
or 2-methoxycarbonylmethyl-4-methylanilinocarbonylme-thyl,
1-(2-methylanilinocarbonyl)-ethyl, (2-ethoxycarbonyl-4-
methylthien-3-ylaminocarbonyl)-ethyl, 2,3-dianilinocarbonyl-
oxypropyl, 4-n-propyl- or 4-n-butylbenzoylethyl, 4-phenoxy-
methylphenyl-n-butyl, 4-n-butoxyphenoxy-n-propyl, 2-n-
butylquinol-8-yloxymethyl or 8-benzoyloxycarbonyl-1,2,3,4-
tetrahydronaphth-2-yl group, and the hydrophilic group
is lower alkylamino, cyclohexylamino, l-methylpiperid-2-yl,
piperid-l- or -2-yl or morpholin-l-yl, neuroleptics or
thymoleptics in which the nonpolar, hydrophobic group Ra in
the formula 1 is lower alkyl or hydroxy-lower alkyl that
is substituted by 2-cyano-, 2-methoxy-, 2-chloro-, 2-tri-
fluoromethyl-, 2-methylthio-, 2-acetyl- or 2-ethyl-10H-
phenothiazin-10-yl, 9H-acridin-10-yl, 5H-dibenzo[b,f]azepin-
-5-yl, 7-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl,
5, 10-dihydro-5-methyl-11-dibenzo[b,e]-1,4-diazepin-11-
onyl, 2-chloro-, 2-trifluoromethyl- or 2-dimethyl-amino-
sulphonyl-9H-thioxanthen-9-ylidene, 10,11-dihydro-5H-
dibenzo[a,d]cyclohepten-5-yl or by 10H-pyrido[3,2-b]-
[1,4]benzothiazin-10-yl, and the polar, hydrophilic group
represents amino, lower alkylamino, di-lower alkylamino,
tri-lower alkylamino, piperidino or 4-hydroxyethyl-
piperazino, antidepressants having a tertiary amino group,
thymeretics having a primary or methyl- and propargyl-
substituted tertiary amino group,
sedatives in which the hydrophobic group Ra in the formula 1
is the 2-(7-chloro-5-_-fluorophenyl-1,3-dihydro-2H-1,4-
benzodiazepin-2-on-1-yl)-ethyl radical and the hydrophilic
group is diethylamino, psychodysleptics having a .beta.-phenyl-
ethylamine structure, psychodysleptics in which the

- 65 -
hydrophobic group Ra in the formula 1 is an ethyl
radical substituted by a 3-indole radical, psycho-
dysleptics in which Ra and Rb in the formula 1
together with the nitrogen atom form a morpholine or
pyrrolidine ring that is substituted by 1,3-lower alkylene,
anticholinergics having an atropine structure,
anticholinergics (agents against Parkinson's Disease)
of the formula
<IMG> (1.4)
in which R represents cyclohexyl, cyclopentyl, phenyl
or norborn-5-en-2-yl, and analogues, anticholinergics
having a tertiary amino group, central analeptics having
a morpholine group, psychoanaleptics having a 4-chloro-
phenoxyacetoxyethyl group as hydrophobic group and a
dimethylamino group as hydrophilic group, vasodilatators
having a tertiary amino group, appetite suppressants
having an amphetamine structure, muscle relaxants having a
hydrophobic group and several quaternary amino groups,
neurotropic spasmolytics having quaternary amino groups,
musculotropic spasmolytics having tertiary amino groups,
4-aminoquinoline antirheumatics, anti-oestrogens having a

- 66 -
tertiary amino group, histamine H1-receptor
antagonists (antihistamines) having an ethylenediamine
group, a 2-aminoethanol group or a 3-aminopropane
group, sympathomimetics of the formula
<IMG> (1.5)
in which R1, R2, R3, R4 and R5 have the following
meanings:
<IMG>

- 67 -
<IMG>
.beta.-receptor blockers of the formula:
<IMG>
in which R1, R2 and R3 have the following meanings:

- 68 -
<IMG>
.beta.-blockers having as hydrophobic group the naphthyloxy,
indolyloxy, 2-methylindolyloxy, 1,2,3,4-tetrahydro-
naphth-2,3-diol-1-yl or 1,2,3,4-tetrahydronaphth-5-on-1-
yl radical, .beta.-blockers in which the segment
<IMG>
has been replaced by

- 69 -
<IMG>
compounds of the reserpine type, tetracycline antibiotics
of the formula
<IMG> (1.7)
in which R1 represents hydrogen or pyrrolidin-1-
ylmethyl, R2 represents hydrogen or hydroxy, R3
represents hydrogen, hydroxy or methyl, R4 represents
hydrogen or methyl, and R5 represents hydrogen,
chlorine or dimethylamino, antimalarial agents of the
quinine type, and analogues having an 8-aminoquinoline, a 4-
aminoquinoline, a 9-aminoacridine, a 1,3,5-triazine or pyrimidine
structure, antischistosomatics in which the hydrophobic, non-polar
group is optionally 6-chloro-,4-methyl- or 4-hydroxymethyl-substituted
xanthonyl or thioxanthonyl, and the hydrophilic, polar
group is diethylamino, antiviral agents of the cyclic
amines type, and glucocorticoids that are esterified in
the 21-position by an amino acid, or as carboxylic acid
salts of the formula 2 having biological activity or
carboxylic acids that can be converted into them by
salt formation, salts of glucocorticoids that are
esterified in the 21-position by a dicarboxylic acid,
short-term narcotics of the 3,20-dioxo-5.beta.-pregnane type
that can be esterified by succinic acid, salts of

- 70 -
choleritics, analgesically active salts of substituted
phenylacetic acids or 2-phenylpropionic acids,
analgesically active anthranilic acid derivatives of
the formula
<IMG> (2.1)
in which R1, R2 and R3, independently of one
another, each represents hydrogen, methyl, chlorine or
trifluoromethyl, analgesically active anilino-
substituted nicotinic acid derivatives, analgesically
active heteroarylacetic acids or 2-heteroarylpropionic
acids having a 2-indol-3-yl or pyrrol-2-yl radical,
analgesically active indenylacetic acids, analgesically
active heteroaryloxyacetic acids, prostanoic acids that
stimulate the smooth musculature, penicillanic acid and
cephalosporanic acid derivatives having antibiotic
action with 6.beta.- or 7.beta.-acylamino groups, which are present
in fermentatively, semi-synthetically or
totally synthetically obtainable 6.beta.-acylamino-
penicillanic acid or 7.beta.-acylaminocephalosporanic acid
derivatives or 7.beta.-acylaminocephalosporanic acid
derivatives modified in the 3-position, and other .beta.-
lactam antibiotics, antineoplastics having a 4-[bis-(2-
chloroethyl)-aminophenyl]-butyric acid structure, or
antineoplastics having two carboxy groups, or, as compounds
of the formula 3, neurotransmitters in which

- 71 -
the hydrophobic group is methyl substituted by
hydroxyphenyl, thyroid hormones having iodine-
substituted phenyl radicals, or antineoplastics having
an amino acid structure, or, as a compound of the
formula 4, betamethasone disodium phosphate, dexamethasone
disodium phosphate, cortisone phosphate,
hydrocortisone phosphate, prednisolone disodium
phosphate or paramethasone-21-disodium phosphate, or, as
salt-type compounds having a hydrophobic group and a
hydrophilic imidazoline, imidazolidine or hydrazino
group, salts of anti-depressantly active hydrazine
derivatives, for example .alpha.-sympathomimetics having an
imidazoline structure, .alpha.-sympatholytics having an
imidazoline structure, centrally active antihyper-
tensives having an imidazoline structure, or
vasodilatators having a hydrazino group, and (II), as
the phospholipid, a compound of the formula
<IMG> (5)
in which both radicals R1 and R2 represent alkyl,
alkenyl, alkoxy, alkenyloxy or acyloxy each having from
10 to 20 carbon atoms, R3 represents hydrogen or
C1-C4-alkyl, and R4 represents hydrogen,
substituted C1-C7-alkyl, C1-C7-alkyl or a
carbohydrate radical having from 5 to 12 carbon atoms,
or a salt thereof.
5. Process according to claim 4, characterised in

- 72 -
that there are homogeneously mixed and dispersed (I),
as the substituted ammonium compound or as the
corresponding amino compound that can be converted into
the ammonium compound by salt formation, acetylcholine
chloride, methacholine chloride, carbachol, muscarine,
pilocarpine, arecoline, phyostigmine, neostigmine,
pyridostigmine bromide, serotonin, histamine,
tryptamine, bufotenine, psilocybin, morphine,
hydromorphone, oxymorphone, levorphanol, codeine,
hydrocodone, oxycodone, nalorphine, naloxone,
naltrexon, buprenophine, butorphanol, nalbiphine,
pholcodine, pentazocine, ketamine, metazocine,
pentazocine, cyclazocine, pethidine, cetobemidon,
alphaphrodine, ethoheptazine, prodilidine, profadol,
methadone, normethadone, isomethadone, dipipanone,
phenadoxone, dimephethanol, dextromoramide,
D-propoxyphene, 1-benzyl-2-dimethylaminomethyl-1-
propanoyloxytetralin, tramadol, dimethylthiambutene,
diampromide, phenampromide, propiram, tilidine, meto-
pholine, etonitazene, ergotamine, dihydroergotamine,
dihydroergocryptine, methysergide, lisuride, dimeto-
tiazin, dizotifen, oxetoron, cyproheptadine, procaine,
chloroprocaine, hydroxyprocaine, propoxycaine, oxy-
buprocaine, propoxymetacaine, piridocaine, leucino-
caine, butacaine, tetracaine, hydroxytetracaine,
cornecaine, edan, piperocaine, cyclomethycaine,
parethoxycaine, stadacain, cinchocaine, lidocaine,
pyrrocaine, granocaine, butanilicaine, tolycaine,
mepivacaine, bupivacainel prilocaine, carticaine,
dipiperidon, propicocaine, dyclonine, pramocaine,
fomocaine, quinisocaine, profenamine, promethazine,
periciazine, perimethazine, chlorpromazine, per-
phenazine, prochlorperazine, triflumpromazine, tri-
fluoperazine, fluphenazine, thioridazine, mesoridazine,
piperacetazine, acetophenazine, ethymemazine, di-

- 73 -
methacrine, opipramol, clomipramine, imipramine,
desimipramine, trimipramine, chloroprothixene, thio-
thixene, amitriptyline, nortriptyline, doxepin,
thiepin, protriptyline, prothipendyl, femoxetin,
citalopram, zimelidine, trebenzomin, viloxazine,
nomifensine, femoxetin, tranylcypromine, pargyline,
etryptamine, flurazepam, mescaline, N.alpha.,N.alpha.-dimethyl-
tryptamine, bufotenine, psilocin, psilocylein, scopol-
amine, atropine, benzatropin, trihexyphenidyl,
cycrimine, pridinol, biperidin , procyclidine,
caramiphen, phenglutarimide, orphenadrine, chlor-
phenoxamine, metixen, doxapram, amphetamine, meth-
amphetamine, propylhexedrine, prolintane, fencamfamine,
methylphenidol, pipradrol, phenmetrazine, diethyl-
propion, meclofenoxat, naftidrofuryl, dexamphetamine,
phentermin, chlorphentermine, fenfluramine, amfe-
pramone, phenmetrazine, phendimetrazine, tubocumarin,
alcuronium chloride, gallamin triethiodide, hexa-
carbacholine bromide, pancuronium bromide, suxa-
methonium chloride, decamethonium bromide, scopolamine
butyl bromide, bevonium methyl sulphate, valethamate
bromide, methanteline bromide, camylofine, hexahydro-
adiphenine, adiphenine, fencarbamide, benzyclamine,
ditaxol, chloroquine, tamoxifen, ethamoxytriphetol,
phenbenzamine, tripelenamin, chlorpyramine, mepyramine,
metaphenilene, metapyrilene, chloropyrilene, hist-
pyrroclin, bamipin, thenalidine, clemizole, meth-
dilazine, isothipendyl, oxomenazine, diphenhydramine,
medrylamine, chlorophenoxamine, silachlorophenoxamin,
carbinoxamine, diphenpyraline, clemastine, ametho-
benzepine, pheniramine, chlorophenamine, bromo-
pheniramine,triprolidine, cycliramine, phenindamine,
dimetindene, cyproheptadine, ketotifen, epinephrine
(adrenaline), norepinephrine (noradrenaline), dopamine,
nordefrin, ethylnorepinephrine, isoprenaline, iso-

- 74 -
ethorine, metaproterenol, orciprenaline, metaraminol,
phenylephrine, hydroxyamphetamine, methoxyphenamine,
methoxamine, albuterol, ephedrine, norephedrine,
fenfluramine, phenylpropanolamine, pholedrine,
tyramine, dichloroisoprenaline, norfenefrine,
octopamine, etilefrin, acebutolol, atenolol, meto-
prolol, toliprolol, alprenolol, oxprenolol, bunitrolol,
bupranolol, talinolol, phenbutolol, bufetolol, varbian
(R,S- or S-form), propanolol, indenolol, pindolol,
mepindolol, nadolol, bunolol, sofalol, nifenalol,
cabetalol, bufenalol, reserpine, rescinnamine,
syringopine, chlorotetracycline, oxytetracycline,
tetracycline, demethylchlorotetracycline, metacycline,
doxycycline, minocycline, rolitetracycline, quinine,
conquinidine, quinidine, cinchonine, pamaquine,
primaquine, pentaquine, chloroquine, santoquine,
hydroxychloroquine, amodiaquine, mepacrin, biguanid-
1,3,5-triazin, proguanil, bromoguanil, chloroproguanil,
nitroguanil, cycloguanilembonate, pyrimethamine, tri-
methoprim, lucanthone, hycanthone, miracil A or B,
amantadine, cyclooctylamine, rimantadin, prednisolone
diethylaminoacetate, and (II), as the phospholipid of
the formula 5, natural lecithin (R3 = hydrogen and
R4 = 2-trimethylammonium ethyl), natural cephalin
(R3 = hydrogen, R4 = 2-ammonium ethyl) having
different acyloxy radicals R1 and R2, synthetic
lecithin or cephalin having different or identical
acyloxy radicals R1 and R2, natural phosphatidyl
serine (R3 = hydrogen, R4 = 2-amino-2-carboxyethyl)
having different acyloxy radicals R1 and R2,
synthetic phosphatidyl serine having different or
identical acyloxy radicals R1 and R2, or natural
phosphatidic acid (R3 and R4 = hydrogen having
different acyloxy radicals R1 and R2).

- 75 -
6. Process according to claim 4, characterised in
that there are homogeneously mixed and dispersed, as
the substituted ammonium compound or as the
corresponding amino compound that can be converted into
the ammonium compound by salt formation, a compound
selected from the group of the acid addition salts of
antidepressants of the formula
<IMG> (1.8)
in which R1 represents lower alkyl, for example
methyl, R2 represents lower alkylene or hydroxy-
lower alkylene, and n represents 0 or 2, acid
addition salts of antidepressants of the formula
<IMG> (1.9)

- 76 -
in which R1 represents lower alkyl, A represents the
group <IMG>, oxygen or sulphur, and R2 represents
hydrogen or cyano, acid addition salts of anti-
depressants of the formula
<IMG> (1.10)
in which R1 represents lower alkylamino-lower alkyl,
di-lower alkylamino-lower alkyl or 3-(4-(2-hydroxy-
ethyl)-piperazin-1-yl)-n-propyl and A represents
ethylene or vinylene, or acid addition salts of
amphetamine, methamphetamine, benzphetamine, propyl-
hexedrine, prolintan, fencamfin, methylphenidate,
pipradrol, phenmetrazine, adiphenine, epinephrine,
norepinephrine, dopamine, nordefrin, ethyl-
norepinephrine, isoprenaline, isoethorine, meta-
proterenol, orciprenaline, metaraminol, phenylephrine,
hydroxyamphetamine, methoxyphenamine, ephedrine,
norephedrine, pholedrine, tyramine, norfenefrin,
octopamine, acebutolol, atenolol, toliprolol,
alprenolol, oxprenolol, bunitrolol, bupranolol,
talinolol, phenbutolol, bufetolol, varbian (R,S-form
and S-form), reserpine, rescinnamine, syringopine or
prednisolone diethylaminoacetate, and (II), as the
phospholipid of the formula 5, natural lecithin or
cephalin, synthetic 1-palmitoyl-2-oleoyl lecithin or
cephalin, dipalmitoyl, distearoyl, diarachinoyl,
dioleoyl, dilinoyl or dilinoleyl lecithin or cephalin,
natural phosphatidyl serine, synthetic 1-palmitoyl-2-

- 77 -
oleoylphosphatidyl serine, dimyristoyl- or dipalmitoyl-
phosphatidyl serine, or natural phosphatidic acid.
7. Process according to claim 4, characterised in
that there are homogeneously mixed and dispersed, as
the substituted ammonium compound of the formula 1 or
as the corresponding amino compound that can be
converted into the ammonium compound by salt fomation,
1-(2R-2-hydroxy-3-methylaminopropyl)dibenzo[b,e]bi-
cyclo[2.2.2]octadiene, and the 2R,S-isomeric mixture,
maprotiline, benzoctamine, 3-methyldibenzo[2,3:6,7]-
oxepino[4,5-d]azepine hydrochloride, 7-cyano-3-methyl-
2,3,4,5-tetrahydro-1H-dibenzo[2,3:6,7]-thiepino[4,5-
d]azepine methanesulphonate, 3,10-dimethyl-1,2,3,4,5,10-
hexahydrodibenzo[b,f]azepino[4,5]azepine maleate,
clomipramine, opipramol, desipramine, imipramine or
imipramine N-oxide, ephedrine, norephedrine, 1-iso-
propylamino-3-[4-(2-methylthioethoxy)-phenoxy]-propan-2-
ol, 1-isopropylamino-3-(2-pyrrol-1-ylphenoxy)-propan-2-
ol, oxprenolol, prenalterol, adiphenine, prednisolone
diethylaminoacetate, or reserpine, and (II), as the
phospholipid of the formula 5, natural lecithin or
cephalin, synthetic 1-palmitoyl-2 oleoyl lecithin or
cephalin, dipalmitoyl, distearoyl, diarachinoyl,
dioleoyl, dilinoyl or dilinoleyl lecithin or cephalin,
natural phosphatidyl serine, synthetic 1-palmitoyl-2-
oleoylphosphatidyl serine, dimyristoyl- or dipalmitoyl-
phosphatidyl serine or natural phosphatidic acid.
8. Process according to claim 4, characterised in
that there are homogeneously mixed and dispersed, as
the carboxylic acid salt or the carboxylic acid
compound that can be converted into the carboxylic acid
salt by salt formation, methylprednisolone sodium
succinate, prednisolone sodium succinate, 3,20-dioxo-5.beta.-

- 78 -
pregnane, hydroxydione succinate sodiun, 11,20-dioxo-3.alpha.-
hydroxy-5.alpha.-pregnane, alphadolon, a cholic acid or
deoxycholic acid salt, alclofenac, ibufenac, ibuprofen,
clindanac, fenclorac, ketoprofen, fenoprofen,
indoprofen, fenclofenac, diclofenac, flurbiprofen,
pirprofen, naproxan, benoxaprofen, carprofen,
cicloprofen, mefenamic acid, flufenamic acid,
tolfenamic acid, meclofenamic acid, milflumic acid,
clonixin, flunixin, indometacin, oxmetacin, intrazol,
acemetazin, cinmetacin, zomepirac, tolmetin, colpirac,
tiaprofenic acid, benzadac, PGE2 (dinoprostone),
PGF2.alpha. (dinoprost), 15 (S)-15-methyl-PGE2, 15 (S)-15-
methyl-PGF2a(carboprost), (?)15 (Xi)-15-methyl-13,14-
dihydro-11-deoxy-PGE1 (deprostil), 15 (S)-15-methyl-
11-deoxy-PGEl (doxaprost), 16,16-dimethyl-PGE2, 17-
phenyl-18,19,20-trinor-PGF2a, 16-phenoxy-17,18,19,20-
tetranor-PGF2a or N-methylsulphonyl-16-phenoxy-
17,18,19,20-tetranor-PGF2a(sulproston), nalixidic
acid, cinoxacin, oxolinic acid, pironidic acid,
pipenidic acid, penicillin G or V, phenethicillin,
propicillin, nafcillin, oxacillin, cloxacillin,
dicloxacillin, flucloxacillin, cyclacillin, epicillin,
mecillinam, methicillin, azlocillin, sulbenicillin,
ticarcillin, mezlocillin, piperacillin, carindacillin,
azidocillin, ciclazillin, cefaclor, cefuroxime,
cefazlur, cephacetrile, cefazolin, cephalexin,
cefadroxil, cephaloglycin, cefoxitin, cephaloridine,
cephsulodin, cefotiam, ceftazidine, cefonicid,
cefotaxime, cefmenoxime, ceftizoxime, cephalothin,
cephradine, cefamandol, cephanone, cephapirin,
cefroxadin, cefatrizine, cefazedone, ceftrixon,
ceforanid, moxalactam, clavulanic acid, nocardicine A,
sulbactam, aztreonam, thienamycin, chlorambucil or
methotrexate, and, (II), as the phospholipid of the
formula 5, natural lecithin or cephalin, synthetic 1-

- 79 -
palmitoyl-2-oleoyl lecithin or cephalin, dipalmitoyl,
distearoyl, diarachinoyl, dioleoyl, dilinoyl or
dilinoleyl lecithin or cephalin, natural phosphatidyl
serine, synthetic 1-palmitoyl-2-oleoylphosphatidyl
serine, dimyristoyl- or dipalmitoyl phosphatidyl serine
or natural phosphatidic acid.
9. Process according to claim 8, characterised in
that there are homogeneously mixed and dispersed, as
the carboxylic acid salt or the carboxylic acid that
can be converted into the carboxylic acid salt by salt
formation, the sodium salts of diclofenac and pirprofen,
and (II), as the phospholipid of the formula 5, natural
lecithin or cephalin, synthetic 1-palmitoyl-
2-oleoyl lecithin or cephalin, dipalmitoyl, distearoyl,
diarachinoyl, dioleoyl, dilinoyl or dilinoleyl lecithin
or cephalin, natural phosphatidyl serine, synthetic 1-
palmitoyl-2-oleoylphosphatidyl serine, dimyristoyl- or
dipalmitoyl-phosphatidyl serine or natural phosphatidic
acid.
10. Process according to claim 1,
characterised in that the homogeneous mixture is prepared
by lyophilisate or film formation.
11. A pharmaceutical composition comprising an aqueous
dispersion wherein the dispersed phase contains a pharma-
ceutically active substance encapsulated within a uni-
lamellar liposome prepared according to the process of
claim 1.

- 80 -
12. A pharmaceutical composition comprising an aqueous
dispersion wherein the dispersed phase contains a pharma-
ceutically active substance encapsulated within a uni-
lamellar liposome prepared according to the process of
claim 1 and pharmaceutically acceptable carriers.

Description

4~6
-- 1 --
~-14770/+
Process for the manufacture of pharmaceutical
compositions containing unilamellar liposomes
:
The present invention relates to a novel, advanta-
geous process for the manufacture of pharmaceutical
compositions containing unilamellar liposomes and to
the use of the pharmaceutical compositions obtainable
according to the process.
Liposomes have been described in the literature in
numerous public~ations. ~any investigations are
concerned witb their structure and use. ~ distinction
is made between unilamellar liposomes having a double
layer of lipids and multilamellar liposomes having
several double layers of lipids arranged in an onion
skin-like ~annerl
Unil~mellar liposomes have a diameter of approxi-
mately from 2.0 x 10-8 to 5.0 x 10~6m, preferably
approximately from 2.0 x 10 to 3.0 x 10 m. The
spherical shell consists of a double layer of lipid
components, for example amphiphatic lipids, for example
phospholipids, for example lecithin, cephalin or
phosphatidic acid, and, optionally, neutral lipids, for
example cholesterol. This ~ouble layer surrounds an
~;, ,,b
' ~ 1

~2~6~
-- 2
interior space which con-tains an aqueous phase with a
compound to be encapsulated, it being possible for the
compound to be encapsulated to be present in the
aqueous phase and/or in the double layer, depending
upon the structure of the compound and other
parameters, such as temperature or concentration~
There is a great deal of interest in the
therapeutic use of liposomes as carriers for active
ingredients of widely varied kinds. ~ccordingly,
liposoTles have been proposed as carriers for proteins,
for example antibodies or enzymes, hormones, vitamins
or genes or, for analytical purposes, as carriers for
labelled compounds. An example that may be mentioned
is US Patent Specification No. 3 993 754 which relates
to a chemotherapeutic process in the treatment of
tumour cells using liposomes as carriers.
Small unila~iellar liposomes (~UL) having a
diameter of approximately fro~ 2.0 x 10 8 to
1.O x 1û~7m are especially suitable for transporta-
tion through barriers in the organism that are
impermeable to large liposomes, for example through
"windows" in fenestrated capillaries, lymp'n node tissue
and interstitial spaces of various tissues.
The active ingredient in question is encapsulated
either du~ing the formation of the liposomes or subse-
quently by diEfusion. The preparation of liposomes and
the encapsulation of the active ingredients can be
effected by various methods and are described in a
synoptical article by Kaye, St. 13./ Cancer Treatment
Reviews (1981), 8, 27-50. Further !nethods of
preparing liposomes for the purpose of encapsulating
active ingredients are also described by Barenholz
et al., in Biochemistry, Vol. 16, No. 12, 2806-2810,
and also in German Offenlegungsschriften (l)OS)
28 l9 855, 29 02 672, 25 32 319 and 28 42 608, in US

-- 3 --
Patent Specification 4 053 585, and in European Patent
Application 36 676.
According to the processes known hitherto, the
lipid components, for example phospholipids, for
example phosphatidic acid, lecithin or cephalin, and,
optionally, neutral lipids, for example cholesterol,
are dissolved in an organic solvent, for example
chloroform or benzene. After concentration by
evaporation there remains a homogeneous layerl for
example a film layer, of the particular lipid
components. The lipid components are subsequently
dispersed in an aqueous phase which contains the
particular active ingredient, for example by shaking.
Unila~ellar liposomes which encapsulate the active
ingredient are formed in subsequent treat~ent with
ultrasound.
European Patent ~pplication 88 046 describes a
process for the manufacture of unilamellar liposomes in
which an aqueous dispersion comprising two different
lipids, for example egg phosphatidic acid and lecithin,
and an active ingredient, for example a mura~yl
peptide, is prepared and a lipid component, foe example
the phosphatidic acid, is converted into the ionic or
dissociated form by altering the pH value of the
aqueous phase.
In the synoptical work "Liposome Technolo~y",
CRC Press 1983, edited by G. Gegoriadis, in Volume II,
Chapter ~, there are described aqueous liposome
dispersions which contain 8-aminoquinoline derivatives.
The preparation is carried out by dissolving a phospho-
lipid, for example dipalmitoyl- or di~yristoyl-
phosphatidyl choline in an organic solvent, for example
chloroform, manufacturing a lipid film and dispersin~
this lipid film in an aqueous phase that contains the
active ingredient, for example primaquine. A dis-

~LZ4~
advantage is the perneability of these liposomes whichis mentioned on page 6~ of this publication and which
causes losses of encapsula-ted active ingredient.
The problem underlying the present invention is to
provide an advantageous and generally applicable
process for the manufac-ture of pharmaceutical composi-
tions having adequate stability an~ a high proportion
o~ encapsulated active ingredient and unilamellar
liposomes.
This problem is solved by the present invention
which relates to a process for the manufacture of
pharmaceutical compositions in the form of aqueous
dispersions containing unilamellar liposomes cornprising
(I) an amphiphatic compound having biological activity
and (II) a phospholipid or an analogous lipid and,
optionally, an additional lipid.
The process according to the invention is charac-
terised in t~at ~I) the amphiphatic compound having
biological activity and (II) the phospholipid or the
analogous lipid and, optionally, the additional lipid
are homogeneously mixed and the resulting homogeneous
mixture is dispersed in an aqueous phase and, if
necessary, the resul~ing aqueous dispersion is neutral-
ised and, if desired, the resulting unilarnellar
liposornes are enriched and/or separated off.
In the context of the description of the present
invention, the general terms e~ployed hereinbefore and
hereinafter preferably have the following meanings:
The term "lower" used in connection with organic
radicals, for exarnple lower alkyl, lower alkylene,
lower alkoxy, lower alkanoyl, etc., means that such
organic radicals, unless expressly defined otherwise,
contain up to and including 7, preferably up to and
including 4, carbon atorns.
TJnless indicated otherwise, the generic names

~?~
proposed by the World Health Organisation (WH~)
(Recommended International Non-proprietary Na~es) are
used for the active ingredients, which names have been
taken frol~ the standard work "Phar~azeutische Chemie"
(E. Schroder, C. Rufer and R. Schmiechen, Thie,~e Verlag
Stuttgart, 1982) and the Merck Index (~enth Edition).
~ n amphiphatic co~pound (I) having biological
activity that is homogeneously mixed with a phospho-
lipid (II) or an analogous lipid and, optionally, an
additional lipid, can be used especially as a
medicament and can be classed, for example,
as a substituted a~monium compound of the for~ula
I a X (~)
N ~ (1)
c
in which
a) Ra represents a hydrophobic group, and Rb,
Rc and Rd, independently of one another, each
represents hydrogen, C1-C4-alkyl, 2-hydroxyethyl,
allyl or cyclo-C3-C6-alkyl-Cl-C3-alkyl, or two of the
radicals Rb, Rc and Rd together represent C4- or C5-
alkylene optionally interrupted by -~N-, -N(C1-C4-
alkyl)-, -N(2-hydroxyethyl)- or by oxygen, or
b) Ra and Rb are two hydrophobic groups or
together represent a hydrophobic group, and Rc and
Rd, independently of one another, each represents
hydrogen, C1-C4-alkyl, allyl or cyclo-C3-C6-alkyl-
Cl-C3-alkyl, or

-- 6
c) Ra~ Rb and Rc toge-ther represent a hydro-
phobic group, and Rd represents hydrogen or
Cl-C4-alkyl, and X~ represents the anion of a
pharmaceutically acceptable acid,
as a carboxylic acid salt of the formula
Ra~COO (~3 Y (~
in which Ra represents a hydrophobic group, and ~
represents the cation of a pharmaceutically acceptable
base,
as an a-amino acid compound of the formula
Rb` Ra
N -
R / COOH (3)
in which Ra represents a hydrophobic group, and Rb
and Rc, independently of one another, each represents
hydrogen or C1-C4-alkyl,
as a phosphoric acid monoest~r of the formula
c)/o ~ Y ~
Ra ~ ~~ P\
O ~ Y
(4)
in which Ra represents a hydrophobic group and ~
represents the cation of a phar~aceutically acceptable

4~
-- 7 --
base, or
as an acid addition salt of a compound having a
hydrophobic ~roup R~ and an imidazoline, inidazoli-
dine or hydrazino group as hydrophilic group.
In a substituted ammoniu~ compound of the formula
1 that can be used as a medicalnent, in case a) the
hydrophobic group Ra is an aliphatic hydrocarbon
radical that can be interrupted by an oxygen or sulphur
atoln, may contain the groups -C(=O)-, -0-~(=3) ,
-C(=3)-NH-, -O-C(=O)-NH- or hydroxy, and can be substi-
tuted by from 1 to 3 optionally substituted, mono-
cyclic, aliphatic or aromatic hydrocarbon radicals, by
an optionally substituted, bi- or tri-cyclic, aromatic
or partially saturated hydrocarbon radical, by an
optionally substituted, monocyclic, aromatic, partially
saturated or saturated heterocycle or by an optionally
substituted, bi- or tri-cyclic, aromatic, partially
saturated or benzo-fused heterocycle.
The hydrophobic group Ra can also be an
optionally substituted, monocyclic, aliphatic or
aromatic hydrocarbon radical or a bicyclic, aliphatic
or benzo-fused hydrocarbon radical. The hydrophilic
group is, or example, a group of the fonnula
N ~
R / ~ \ Rd
~c

-- 8
in which Rb, Rc and Rd, independently of one
another, each represents hydrogen, C1-C4-alkyll for
example methyl, ethyl, isopropyl or n-propyl, or 2-
hydroxyethyl, or in which two of the radicals Rb,
Rc and Rd together represent piperidino,
piperazinyl, l-methylpiperazinyl, 1-(2-hydroxy~thyl)-
piperazinyl or morpholino, and the other radical
represents hydrogen.
In a substituted ammonium compound of the formula
1 that can be used as a medicament, in case b) ~a and
Rb are two hydrophobic groups, for example two
aliphatic hydrocarbon radicals, which can be substi-
tuted by one or two optionally substituted, monocyclic,
aliphatic or aromatic hydrocarbon radisals or by an
optionally substituted, monocyclic, aromatic, partially
saturated or saturated heterocycle, or Ra and Rb
toget~er represent an optionally substituted,
monocyclic, aromatic, saturated, partially saturated or
benzo-fused heterocycle. The hydrophilic group is a
group of the formula
\ /~
/N\
R \ R
c d
in which Rc and Rd, independently of one another,
each represents hydrogen or C1-C4-alkyl, preferably
methylO
In a substituted ammonium compound of the formula
1 that can be used as a medicament, in case c) R
Rb and Rc form the hydrophobic group and together
represent an optionally substituted, aromatic,
partially saturated or benzo-fused heterocycle. The

- 9
hydrophilic group is a group of the formula
\~ .
-- - Rd
in which Rd represents hydrogen or C1-C4-alkyl,
preferably methyl.
~ is the anion of a pharmaceutically acceptable
acid, for example a mineral acid, for exa~ple the
chloride, hydrogen sulphate or dihydrogen phosphate
ion, the bromide or iodide ion, or the anion of an
organic acid, for example a lower alkanecarboxylic
acid, for example the acetate ion, of an unsaturated
carboxylic acid, for example the fumarate or maleate
ion, of a hydroxy acid, for example the lactate,
tartrate or citrate ion, or of an aromatic acid, for
example the salicylate ion.
An amphiphatic, substituted ammonium compound of
the formula 1 that can be used as a medicament, or the
corresponding amino compound that can be converted into
the ammonium compound by salt formation, is~ for
example, a compound selected from the group comprising
parasympathomimetics having ~uaternary or tertiary
ammonium groups, for example acetylcholine chl.oride,
methacholine chloride, carbachol, muscarine,
pilocarpine or are~oline; choline esterase inhibitors
having two tertiary amino groups, for example
phyostigmine, or having a quaternary ammoniu.~ group,
for example neostigmine bromide or pyridostigmine
bromide; neurotransmitters having a primary amino
group, for example serotonin or histamine; serotonin
antagonists in which the hydrophobic group has an
indol-3-ylethyl structure and the hydrophilic group is
a primary or tertiary amino group, for example
tryptamine, bufotenine or psilocybin; analgesics of the
morphine type having a tertiary amino group and their

~z~
- l o -
antagonists, for exa~ple of the formula
.D \.
11
O \ ; - R3 (1-l)
R / ~ ~
in which R~, R2 and R3 have the meanings given in
the followin~ list:
Rl R2 R3 Name
-OH -OH -CH3 Morphine
-OH =O -CH3 Hydromorphone
-OH =O -CH3 Oxymorphone
-OH -H -CH3 Levorphanol
-OCH3 -OH -CH3 Codeine
-OCH3 = -CH3 Hydrocodone
-OCH3 = -C~3 Oxycodone
-OH -OH allyl Nalorphine
-OH =O allyl Naloxone
-OH =O cyclopropylmethyl Naltrexone
-OH -OCH3 cyclopropylmethyl Buprenophine
-OH -H cyclobutyl~ethyl Butorphanol
-OH -O~ cyclobutylmethyl Nalbuphine
-2-(morpholin-
1-yl)-ethyl) -OH -CH3 Pholcodine
analgesics of the benzomorphan type havin~ a tertiary
amino group, for example metazocine, pentazocine or
cyclazocine; analgesics of the pethidine type, for

6~46
example pethidine, cetobemidon, alphaphrodine,
ethoheptazine, prodili~ine or profadol; ~nalgesics of
the methadone type in which the hydrophobic group is,
for example, a l,l-diphenyl-l-lower alkyl-2-butanone
radical and the hydrophilic group is dimethylamino,
morpholino or piperidino, for example hydrochlorides of
compounds o the formula
\ ~ / 2 5
'=' \ /
\ / / 2 ~ \
(1.2)
in which R1 represents hydrogen or methyl, R2 and
R3 each represents methyl, or R2 and R3 together
represent morpholino or piperidino, for example
methadone, normethadone, isomethadone, dipipanone,
phenadoxor.e or analogues thereof having a pseudo-
methadone structure, for example dimephethanol or
dextromoramide; analgesics similar to morphine having
an aliphatic or cycloaliphatic tertiary amino group,
for example D-propoxyphene, l-benzyl-2-dimethylamino-
methyl-l-propanoyloxytetralin, tramadol,
dimethylthia~butene, diampromide, phenampromide,
propiram, tilidine, metopholine or etonltazene;
analgesics of the benzimidazole type, for example of
the formula

~Z~4~
1 2
R1~ CH - ~ ~;
7 I CH3
IH2 C~ - N
c~3
(1.3)
in which R1 represents 5-, 6- or 7-nitro, R2
represents hydrogen, 3'- or 4'-methoxy, 4'-ethoxy,
4'-isopropoxy, 4'-methyl or 4'-chloro; local
anaesthetics in which Ra and Rb in the formula 1
together with the nitrogen form a piperidyl radical
that is substituted by a lower alkylene bridge, for
example 1,3-propylene, tha~ is itself substituted by a
methoxycarbonyl and a benzoyloxy group, for example
pseudococaine or cocaine; local anaesthetics in which
the hydrophobic group Ra in the formula (1) is, for
example, a 4-aminobenzoyloxyethyl, 4-amino-2-chloro-,
2-n-butoxy- or 2-hydroxy-benzoyloxyethyl,
4-amino-3-n-butoxybenzoyloxyethyl/ 3-amino-4-n-butoxy-
benzoyloxyethyl, 2-aminobenzoyloxyethyl, 2-(4-amino-
benzoyloxy)-6-methyl-n-p~ntyl, 4-aminobenzoyloxy-n-
propyl, 4-n-butylaminobenzoyloxyethyl, 4-n-butyl-2-
hy~roxybenzoyloxyethyl, 3-(4-n-propoxybenzoyloxy-2-
hydroxy)-propyl, 2-n-benzoyloxy-n-propyl,
2-(2-acetoxybenzoyloxy)-n-propyl, benzoyloxy-n-propyl,
4-cyclohexyloxyhenzoyloxysthyl, 4-ethyl- or 4-n-butyl-
benzoyloxyethyl, 2-n-butoxy~uinol-4-ylcarbonyloxyethyl,
2,4-di~ethylanilinocarbonylmethyl, 2-ethyl-, 2-chloro-
or 2-methoxycarbonylethyl-4-methylanilinocarbonyl-
methyl, 1-(2-methylanilinocarbonyl)-ethyl, (2-ethoxy-
carbonyl-4-methylthien-3-ylaminocarbonyl)-ethyl,

~64~6
- 13 -
2,3-dianilinocarbonyloxy~ropyl, 4-n-propyl- or
~-n-butyl-benzoylethyl, 4-phenoxymethylphenyl-n-butyl,
4-n-butoxyphenoxy-n-propyl, 2-n-butylquinol-8-
yloxy.nethyl or 8-benzoyloxycarbonyl-1,2,3,4-tetra-
hydronaphth-2-yl group, and the hydrophilic group is
lower alkylamino, for example methyl-, ethyl-,
isopropyl- or n-butyl-amino, di-lower alkylamino, for
example dimethyl-, diethyl- or di-n-propyl-amino,
cyclohexylamino, l-methylpiperid-2-yl, piperid-l- or
-2-yl or morpholin-l-yl, for example local
anaesthetics, neuroleptics and/or thymoleptics ~hat
have become known under the names procaine,
chloroprocaine, hydroxyprocaine r propoxycaine,
oxybuprocaine, propox~netacaine, piridocaine,
leucinocaine, butacaine, tetracaine, hydroxytetracaine,
cornecaine, edan, piperocaine, cyclomethycaine,
parethoxycaine, stadacain, cinchocaine, lidocaine,
pyrrocaine, granocaine, butanilicaine, tolycaine,
mepivacaine, bupivacaine, prilocaine, carticaine,
dipiperidon, propicocaine, dyclonine, pramocaine,
fomocaine or quinisocaine, in which the non-polar,
hydrophobic group Ra of the ~ormula 1 is a lower
alkyl radical, for example ethyl, n-propyl, isopropyl
or n-butyl, or hydroxy-lower alkyl, for example
2-hydroxy-n-propyl, that is substituted by 2-cyano-,
2-methoxy-, 2-chloro-, 2-trifluoromethyl-,
2-methylthio-, 2-acetyl- or 2-ethyl-lOH-pheno-thiazin~
10-yl, 9H-acri~in-10-yl, 5H-dibenzo[b,]azepin-5-yl,
7-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl,
5,10-dihydro-5-methyl-11-dibenzo[b,e]-1,4-diazepin-11-
onyl, 2-chloro-, 2-trifluoromethyl- or 2-dimethyl-
aminosulphonyl-9H-thioxanthen-9-ylidene, 10,11-dihydro-
5H-dibenzo[a,d]cyclohepten-5-yl or by 10H-pyrido[3,2-
-b]-[1,4]benzothiazin-10-yl, ~nd -the polar hydrophilic
group represents amino, lower alkylamino, for example

~2~6~6
, ~,
methyla~ino, di-lower alkylamino, for example dimQ-thyl-
or diethyl-amino, tri-lower alkylamino, for exa~ple
trimethyl- or triethyl-amino, piperidino or 4-hydroxy-
ethylpiperazino, for example profenamine, promethazine,
periciazine, perimethazine, chlorpromazine,
perphenazine, prochlorperazine, triflumproazine,
trifluoroperazine, fluphenazine, thioridazine,
mesoridazine, piperacetazine, acetophenazine,
ethymemazine, dimethacrine, opipramol, clomipramine,
imipramine, desimipramine, trimipramine,
chloroprothixene, thiothixene, amitriptyline,
nortriptyline, doxepin, thiepin, protriptyline or
prothipendyl; ~ntidepressants having a tertiary a~ino
group selected from the group co~prising citalopram,
zimelidine, trebenzomin~ viloxazine, nomifensine and
femoxetin; thymeretics having a primary or methyl- and
propargyl-substituted amino group, for example
tranylcypromine, pargyline or etryptamine; sedatives in
wbich the hydrophobic group R~ in the formula l is
the 2-(7-chloro-5-o-fluorophenyl-1,3-dihydro 2~-1,4-
benzodiazepin-2-on-l-yl)-ethyl radical and the
hydrophilic group is diethylamino, for example
flurazepam; psychodysleptics having a B-phenylethyl-
amine structure, for example mescaline;
psychodysleptics in which the hydrophobic group Ra in
the formula l is an ethyl radical substituted by a 3-
indole radical, ~or example N~,N-dimethyltrypt-
amine, bufotenine, psilocin or psilocylein:
psychodysleptics in which Ra and Rb in the formula
l together with the nitrogen atom form a morpholine or
pyrrolidine ring that is substituted by 1,3-lower
alkylene, for example scopolamine or atropine;
anticholiner~ics having an atropine structure, for
example benzatropine; anticholinergics (agents against
Parkinson's Disease) of the ~or~ula

i4~
~ CH2 - CH2~ N\ \ ~1.4)
in which R represents cyclohexyl, cyclopentyl, phenyl
or norborn-5-en-2-yl, for example trihe~yphenidyl,
cycrimine, pridinol or biperidin, and analogues, such
as procyclidine; anticholinergics having a tertiary
amino group, for example caramiphen, phenglutarimide,
orphenadrine or chlorphenoxamine; central analeptics
having a morpholine group, for example doxapram;
psychoanaleptics having a phenylaminopropane structure,
for example amphetamine, methamphetamine, propyl-
hexedrine, prolintane, fencamfamine, methylphenidatel
pipradrol or phenmetrazine; psychoanaleptics having a ~-
chlorophenoxyacetoxyethyl group as hydrophobic group
and a dimethylamino group as hydrophilic group, for
example meclofenoxate; vasodilatators having a tertiary
amino groupl for example naftidrofuryl; ~ppetite
suppressants having an amphetamine structurel for
example dexamphetamine, phentermine, chlorophentermine,
fenfluramine, amfepramonel phenmetrazine or phendi-
metrazine; muscle relaxants having a hydrophobic group
and several quaternary amino groups, for example
tubocumarinl alcuronium chloridel gallamine tri-
ethiodidel hexacarbacholine bromidel pancuronium
bromidel suxamethonium chloride or decamethonium
bromide; neurotropic spasmolytics having quaternary
amino groupsl for example scopolamine butyl bromide
bevonium methyl sulphatel valethamate bromide or

~z~
- 16 -
methanteline bromide; musculotropic spasmolytics having
tertiary amino groups, for example camylofine,
hexahydroadiphenine, adiphenine or fencarbamide; 4-
aminoquinoline antirheumatics, for example chloroquine;
anti-oestrogens having a tertiary amino group, for
example tamoxifen or ethamoxytriphetol; histamine Hl-
receptor antagonists (antihistamines) having an
ethylenediamine group, for example phenbenzamine,
tripelenamine, chloropyramine, mepyramine, meta-
phenilen, metapyrilene, chloropyrilene, histapyrrodine,
bamipine, thenalidine, clemizole, methdilazine,
isothipendyl or oxomenazine, a 2-aminoethanol group,
fox example diphenhydramine, medrylamine, chlorophenox-
amine, silachlorophenoxamine, carbinoxamine, diphen-
pyraline, clemastine o.r amethobenzepin, or a 3-amino-
propane group, for example pheniramine,
chlorophenamine, bromopheniramine, triprolidine,
cycliramine, phenindamine, dimetindene, cyproheptadine
or ketotifen; sympathomimetics of the formula
H - CH - IH
Rl R3 4 R5
(1.5)
in which R1, R2~ R3~ R4 and R5 have the following
meanings:

~2~
- 17 -
Rl R2 R3 R4 R5 Na~e
3-OH 4-OH ~OH -~ -CH3 Epinephrine
(Adrenaline)
3-OH 4-OH -OH -H -a Norepinephrine
(Noradrenaline)
3-OH 4-OH -H -H -H ~opamine
3-3H 4-OH -OH -CH -H Nordefrin
3-OH 4-OH 2 5 Ethylnorepine-
phrine
3-OH 4-OH -OH -H -CH(CH3)2 Isoprenaline
3-OH 4-OH -OH -C2H5 -CH(cH3)2 Isoethorine
3-OH 4-OH -OH -H -CH(CH3)2 Metaproterenol
3-OH 5-OH -OH -H -C(CH3)3 Orciprenaline
3-OH -H -OH -CH3 -H Metaraminol
3-OH -H -OH -H -CH3 Phenylephrine
4-OH -H -H -H -H Hydroxy-
amphetamine
2-OCH3 -H -H -CH3 -CH3 Methoxy-
~ ~henamine
2-OCH3 s-~H3 -OH -CH3 -H ~ethoxamine
3-CH20H 4-OH -OH -H -C(CH3)3 ~lbuteLol
-H -H -OH -CH3 -CH3 Ephedrine
-H -H -OH -CH3 -H Norephedrine
3-CF3 -~ -H -CH3 C2 5 Fenfluramine
-H -H -OH -CH3 -H Phenylpropanol-
a~ine
4-OH -~ -OH -CH3 -CH3 Pholedrine
4-OH -H -OH -CH3 -H Tyramine
3-C1 4-Cl -OH -H -C(CH3)3 Dichloro-
isoprenaline
4-OH -H -OH -H -CH3 Norfenefrine
4-OH -a -OH -H -H Octopamine
3-OH -H -OH -H C2H5 Etilefrin,

4~6
- 18 -
B-receptor blockers of the formula:
Rl
D ~. -O-CH2-CH2-CH2-NH - C - CH3 (1.6)
R ~ - . OH R3
in which Rl, R2 and R3 have the followin~ meanings:
Rl R2 R3 Name
:
2-acetyl 4-n-butyryl- H Acebutolol
amino
4-carbamoylmethyl ~ H ~tenolol
4-(2-carbamoylethyl) H H Metoprolol
3-methyl H H Toliprolol
2-allyl H H ~lprenolol
2-allyloxy H H Oxprenolol
2-cyano H methyl Bunitrolol
2-chloro 5-methyl methyl Bupranolol
3-(N-cyclohexyl-
N'-ureido) H methyl Talinolol
2-cyclopentyl H methyl Phenbutolol
2-tetrahydrofur-2-
ylmethoxy H methyl ~ufetolol
2-pyrrol-1-yl H H
4-(2-methylthio-
ethoxy) H H
4-OH H H Varbian,
R,~S-form,
S-form,
~-blockers having a bicyclic, condensed aryloxy
ra~ical, for exa~ple the naphthyloxy, indolyloxy, 2-

~Z~6~L~6
, g
methylindolyloxy, 1,2,3,4-tetrahydronapht'n-2,3-diol-
l-yl or 1,2,3,4-tetrahydronaphth~5-on-1-yl radical, for
exa~ple propanolol, indenolol, pindolol, mepindolol,
nadolol or bunolol, and ~-blockers in which the segment
-~-cH2-cH-NH
OH
has been replaced by
-:)-CH-CH2--~H-,
OH
for example sotalol, nifenalol, labetalol or bufuralol,
compounds having an action on peripheral noradrenaline
storers, for example compounds of the reserpine ty~e,
for example reserpine, rescinnamine or syringopine;
tetracycline antibiotics of the formula
R~ . ~ R3 . N(CH3)2
\./ \./ \/ \.~OH
11 1 1 11
~./ \./ ~. / \ ./ ~CONHRI
OH O O ~ O (1 7)
in which Rl represents hydrogen or pyrrolidin-l-
ylmethyl, R2 represents hydrogen or hydroxy, R3
represents hydrogen, hydroxy or methyl, R4 represents
hydrogen or methyl, and R5 represents hydrogen,
chlorine or dimethylamino, ~or example chlorotetra-
cycline, oxytetracycline, tetracycline, demethylchlor-
tetracycline, metacycline, doxycycline, minocycline or

~2~
- 20 -
rolitetracycline; antilnalarial agents of the qui~ine
type, for example conquinidine, quinidine or cinchonine,
and analogues having an 8-aminoquinoline struc-ture,
for exanple pamaquine, primaquine or pentaquine, a 4-
aminoquinoline or 9-aminoacri~ine structure, for
example chloroquine, santoquin, hydroxychloroquine,
amodiaquin or mepacrine, a 1,3,5-triazine or pyri~idine
structure, ~or example proguanil or pro~ianil; anti-
schistosomatics in which the hydrophobic, non-polar
group is optionally 6-chloro- and/or 4-methyl- or 4-
hydroxynethyl-substituted xanthonyl or thioxanthonyl,
and the hydrophilic, polar group is diethylamino, for
example lucanthone, hycanthone, myracil A or ~;
antiviral agents of the cyclic amines type, for exa~ple
amantadine, cyclooctylamine or rimantadine, and
glucocorticoids that are esterified in the 21-position
by an amino acid, for example prednisolone
diethylaminoacetate.
In a carboxylic acid salt of the formula 2 that
can be used as a medicament, the hydrophobic group Ra
is an aliphatic hydrocarbon radical that can be
substituted by an optionally substituted, monocyclic,
aromatic hydrocarbon radical or by an optionally
substituted, bi- or tri-cyclic, aromatic or partially
saturated hydrocarbon radical, by an optionally
substituted, ~onocyclic, aro~atic or partially
saturated heterocycle or by an optionally substituted,
bi- or tri-cyclic, aromatic, par-tially saturated or
benzo-fused heterocycle or by a steroid radical, or
Ra is an optionally substituted, monocyclic, aromatic
~ydrocarbon radical, an optionally substituted, bi- or
tri-cyclic, aromatic or partially satura-ted hydrocarbon
radical, an optionally substituted, monocyclic,
aro~natic or partially saturated heterocycle or an
optionally subs~i-tuted, bi- or tri-cyclic, aromatic,

~Z4~ 4~
21 -
partially saturated or benzo-fused heterocycle.
The cation ~ of a pharmaceutically acceptable
base is, for example, an alkali metal ion, for example
a lithium, sodium or potassium ion, an alkaline earth
metal ion, for example a magnesium or calcium ion, or
an am~onium or mono-, di- or tri-C1-C4-alkylammonium
ion, for example a trimethyl-, ethyl-, diethyl- or
triethyl-ammoniu~ ion, a 2-hydroxyethyl-tri-C1-C4-
alkylammonium ion, for example cholinyl, or the cation
of a basic amino acid, for example lysine or arginine.
Carboxylic acid salts of the formula 2 having
biological activity or carboxylic acids that can be
converted into them by salt formation are, for example,
salts of glucocor~icoids that are esterified in the
21-position by a dicarboxylic acid, for exa~ple
methylprednisolone sodium succinate, prednisolone
sodium succinate, short-term narcotics oE the
3,20-dioxo-5~-pregnane type that can be esterified by
succinic acid, for example hydroxydione succinate
sodium or 11,20-dioxo-3a-hydroxy-5~-pregnane, for
example alphaxolone, or the 21-compound, for example
alphadolone; salts of choleritics, for example cholic
acid salts or deoxycholic acid salts; analgesics, for
example salts of substituted phenylacetic acids or
2-phenylpropionic acids, for example alclofenac,
ibufenac, ibuprofen, clindanac, fenclorac, ketoprofen,
fenoprofen, indoprofen, fenclofenac, diclofenacO
flurbiprofen, pirprofen, naproxen, benoxaprofen,
carprofen or cicloprofen; analgesically active
anthranilic acid derivatives, for example of the
formula

~2~6~6
- 22 -
. \ / COOH
i1
./ ~ NH
~ . ~ \ / (2.1)
11
~./ \ R3
in which Rl, R2 and R3, independently of one
another, each represents hydrogen, methyl, chlorine or
trifluoromethyl, for example mefenamic acid, flufenamic
acid, tolfenamic acid or meclofenamic acid;
analgesically active anilino-substituted nicotinic
acid derivatives, for example miflumic ~cid, clonixin
or flunixin; analgesically active heteroarylacetic
acids or 2-heteroarylpropionic acids having a
2-indol-3-yl or pyrrol-2-yl radical, for example
indomethacin, oxmetacin, intrazol, acemetazin,
cinmetacin, ~omepirac, tolmetin, colpirac or
tiaprofenic acid: analgesically active indenylacetic
acids, for example sulindac; analgesically active
heteroaryloxyacetic acids, ~or example benzadac,
prostanoic acids that sti~ulate the smooth musculature,
for example P5E2 (dinoprostone), PGF2a (dinoprost),
15 (S)-15-methyl-PSE2, 15 (S)-15-methyl-PGF2a
(carboprost), (~)15 (Xi)-15-methyl-13,14-dihydro-11-
deoxy-P&E1 (deprostil), 15 (S)-15-methyl 11-deoxy-
PGE1 (doxaprost), 16,16-dimethyl-PGE2, 17-phenyl-
18,19,20-trinor-PGF2a, 16-phenoxy-17,18,19,20-
tetranor-PGF2a, for example cloprostenol or
fluprostenol, or N-methylsulphonyl-15-phenoxy-17,18,-
19,20-tetranor-PGF2a(sulproston); bacteriostatics,
for example salts of nalidixic acid derivatives, for

- 23 -
example nalidixic acid, cinoxacin, oxolinic acid,
pironidic acid or pipenidic acid, p~nicillanic acid and
cephalosporanic acid derivatives having antibiotic
activity with o~- or 7~-acylamino groups, which are
present in fermentatively, semi-synthetically or
totally synthetically obtainable 6~-acylamino-
penicillanic acid or 7B-acylaminocephalosporanic acid
derivatives or 7~-acylaminocephalosporanic acid
derivatives modified in the 3-position, for example
penicillanic acid derivatives that have become known
under the names penicillin G or V, phenethicillin,
propicillin, nafcillin, oxacillin, cloxacillin,
dicloxacillin, flucloxacillin, cyclacillin, epicillin,
mecillinam, methicillin, azlocillin, sulbenicillin,
ticarcillin, mezlocillin, piperacillin, carindacillin,
azidocillin or ciclazillin, or cephalosporin
derivatives that have become known under the names
cefaclor, cefuroxime, cefazlur, cephacetrile,
cefazolin, cephalexin, cefadroxil, cephaloglycin,
cefoxitin, cephaloridine, cephsulodin, cefotiam,
ceftazidine, cefonicidr cefotaxime, cefmenoxime,
ceftizoxime, cephalothin, cephradine, cefamandol,
cephanone, cephapirin, cefroxadin, cefatrizine~
cefazedone, ceftrixon or ceforanid, and other ~-lactam
antibiotics, for example moxalactam, clavulanic acid,
nocardicine A, sulbactam, aztreonam or thienamycin, or
antineoplastics having a 4-[bis-(2-chloroethyl)-amino-
phenyl]-butyric acid stru.ture, for example
chlorambucil, or antineoplastics having two carboxy
groups, for example methotrexate.
Compounds of the for~ula 3 having a biological
activity are, for example, neurotransmitters in which
the hydrophobic group is methyl substituted by
hydroxyphenyl, for example L-tyrosine, L-dopa, a-
methyldopa or metirosine, thyroid hormones having

~2~
- 24 -
iodine-substituted phenyl radicals, for example levo-
thyrosine, diiodotyrosine or liothyronine, or anti-
neoplastics having an anino acid structure, for example
melphalen.
In a compound of the formula 4 having biological
activity the non-polar, hydrophobic group Ra is a
glucocorticoid radical and X~ is sodium, for example
betamethasone disodium phosphate, dexamethasone
disodium phosphate, cortisone phosphate, hydrocortisone
phosphate, prednisolone dis~diu~.n phosphate or
paramethasone-21-disodium phosphate.
Salt-type compounds having a hydrophobic group and
an imidazoline, imidazolidine or hydrazino group as
hydrophilic group are, for example, salts of anti-
depressantly active hydrazine derivatives, for example
iproniazid, nialamide, isocarboxazid, phenelzine,
pheniprazine, mebanazine or fenoxypropazine
a-sympathomi~etics having an imidazoline structure, for
example naphazoline, tetryzolin, tramazoline, xylo-
metazoline or oxymetazoline; ~-sympatholytics having an
imidazoline structure, for example phentolamine or
tolazoline, or centrally active antihypertensives
having an imidazoline structure, for example clonidine,
tolonidine or flutonidine, or vasodilatators having a
hydrazino group, for example dihydralazine, hydralazine
or picodralazine.
A phospholipid (II) that is mixed homogeneously
with the amphiphatic compound (I) having biological
activity has, for example, the formula

- 25 -
R O
13 ll
Rl-CH2-C-CH2--P--R4 (5 )
2 OH
in which one of the radicals R1 and R2 represents
hydrogen, hydroxy or C1-C4-alkyl, and the other
radical represents alkyl, alkenyl, alkoxy, alkenyloxy
or acyloxy each having from 10 to 20 carbon atoms, or
both radicals R1 and R2 represent alkyl, alkenyl,
alkoxy, alkenyloxy or acylo~y each having from 10 to 20
carbon atoms, R3 represents hydrogen or C1-C4-
alkyl, ~nd R4 represents hydrogen, optionally
substituted C1-C7-alkyl or a carbohydrate radical
having from 5 to 12 carbon atoms or, if both radicals
R1 and R2 represent hydrogen or hydroxy, R4
represents a steroid radical, or is a salt thereof.
In a phospholipid of the formula 5, R1, R2 or
R3 having the meaning C1-C4-alkyl is preferably
methyl, but may also be ethyl, n-propyl, or n-butyl.
~ lkyl R1 or R2 is preferably straight-chained
with an even number of from 10 to 20 carbon atoms, for
example n-decyl, n-dodecyl (lauryl), n-tetradecyl
(myristyl), n-hexadecyl (cetyl), n-octadecyl (stearyl)
or n-eicosyl (arachinyl).
~ lkenyl R1 and/or R2 is preferably
straight-chained with an even number of from 12 to 20
carbon atoms and a double bond, for example 9-cis-
dodecenyl (lauroleyl), 9-cis-tetradecenyl
(myristoleyl), 9-cis-hexadecenyl (palmitoleinyl),

- 26 -
6-cis-octadecenyl (petroselinyl), 6-trans-octadecenyl
(petroselaidinyl), 9-cis-octadecenyl (oleyl), 9-trans-
octadecenyl (elaidinyl) or 9-cis-eicosenyl
(gadoleinyl).
Alkoxy R1 and/or R2 is preferably straight-
chained with an even number of from 10 to 20 carbon
atoms, for example n-decyloxy, n-dodecyloxy
(lauryloxy), n-tetradecyloxy (myristyloxy), n-
hexadecyloxy (cetyloxy), n-octadecyloxy (stearyloxy)
and n-eicosyloxy (arachinyloxy).
Alkenyloxy R1 and/or R2 is preferably
straight-chained with an even number of from 12 to 20
carbon atoms, for example 9-cis-dodecenyloxy
(lauroleyloxy), 9-cis-tetradecenyloxy (myristoleyloxy),
9-cis-hexadecenyloxy (palmitoleinyloxy), 6-cis-
octadecenyloxy, (petroselinyloxy)~ 6-trans-
octadecenyloxy (petroselaidinyloxy),
9-cis-octadecenyloxy (oleyloxy)l 9-trans-octadecenyloxy
(elaidinyloxy) and 9-cis-eicosenyl (gadoleinyloxy).
Acyloxy R1 and/or R2 is preferably straight-
chained with an even number of from 10 to 20 carbon
atoms, for example alkanoyloxy or alkenoyloxy, prefer-
ably n-decanoyloxy, n-dodecanoyloxy (lauroyloxy),
n-tetradecanoyloxy (myristoyloxy), n-hexadecanoyloxy
(palmitoyloxy), n-octadecanoyloxy (stearoyloxy) and
n-eicosoyloxy (arachinoyloxy).
Alkenoyloxy R1 and/or ~2 is preferably
straight-chained with an even number of from 10 to 20
carbon ato~s, for example 9-cis-dodecenyloxy
(lauroleoyloxy), 9-cis-tetradecenoyloxy
(myristoleoyloxy), 9-cis-hexadecenoyloxy
(pal~itoleinoyloxy), 6-cis-octadecenoyloxy
(petroselinoyloxy), 6-trans-octadecenoyloxy
(petroselaidinoyloxy), 9-cis-octadecenoyloxy
(oleoyloxy), 9-trans-octadecenoyloxy

6~6
~ 27 -
(elaidinoyloxy) and 9-cis-eicosenoyloxy
(gadoleinoyloxy).
Optionally substituted C1-C7-alkyl R~ is,
for example, methyl, ~thyl, isopropyl, n-propyl,
isobutyl or n-butyl which can be subs-tituted by acidic
groupsj for exampl~ carboxy or sulpho, by acidic and
basic groups, Eor exampl~ carboxy and amino, the amino
group bein~ in the a-posi-tion to the carboxy group, by
free or etherified hydroxy groups, it being possible
or two etherified hydroxy groups to be bonded to one
another by a bivalent hydrocarbon radical, for example
methylene, ethyl2ne, ethylidene, 1,2-propylene or 2,2-
propylene, or by halogen, for example chlorine or
bro~ine, by lower alkoxycarbonyl, for example methoxy-
or ethoxy-carbonyl, or by lower alkanesulphonyl, for
example methanesulphonyl.
Substituted Cl-C7-alkyl R4 is, or example,
carboxy-lower alkyl, for example carboxymethyl,
2-carboxyethyl or 3-carboxy-n-propyl, ~-amino-~-
carboxy-lowQr alkyl, for example 2-amino-2-carboxyethyl
or 3-amino-3-carboxy-n-propyl, hydroxy-lower alkyl,
for example 2-hydroxyethyl or 2,3-dihydroxypropyl,
lower alkoxy-lower alkyl, for exa~ple methoxy- or
ethoxy-methyl, 2-methoxyethyl or 3-methoxy-n-propyl,
lower alkylenedioxy-lower alkyl, for example 2,3-
ethylsnedioxypropyl or 2l3-t2,2-propylene)-dioxy-
propyl, or halo-lower alkyl, for example chloro- or
bromo-methyl, 2-chloro- or 2-bromo-ethyl r 2- or 3-
chloro- or 2- or 3-bromo-n-propyl.
Substituted C1-C7-alkyl R4 is preferably
ethyl substituted by tri-lower alkylammoniu.~, ~or
example trimethyl- or triethyl~ammoniu~, for example
2-trimethylammonium-ethyl or 2-ammonium-ethyl, or
for exa.~ple ~-amino-~-carboxy-
lower alkyl, for exa~ple 2-amino-2-carboxyethyl~

~6~6
- 28 -
A carbohydrate ra~ical R4 having fro~ 5 to 12
carbon ato~s is, for example, a natural monosaccharide
radical that is derived fro~ a pentose or hexose
present in the for~ of aldose or ketose.
A pentose present in the form of aldose is, for
example, D-ribose, D-arabinose, D-xylose or D-lyxose.
~ pentose present in the for~ of ketose is, for
example, D-ribulose or D-xylulose.
A hexose present in the form of aldose is, for
example, ~-allose, D-altrose, D-glucose, D-mannose,
D-galactose or D-talose.
A hexose present in the form of ketose is, for
exa~ple, D-psicose, ~-fructose, D-sorbose or
D-tagatose.
~ hexose is preferably present in cyclic form, for
example in the form of pyranose (aldose), for example
~- or ~i-D-fructose. The pyranosyl radical is
preferably esterified by the phosphatidyl group by way
of the hydroxy group located in the 1- or 5-position
and the furanosyl radical is preferably esterified by
way of the hy~roxy group in the 1- or 5-position.
A carbohydrate radical R4 having from 5 to 12
carbon ato~s is also a natural disaccharide radical,
for exa,nple a disaccharide raflical that is for~ed from
two hexoses and which is for~ed, for example, by
condensation of two aldoses, for example ~-glucose or
D-galactose, or an aldose, for example D-glucose, with
a ketose, for example fructose. nisaccharides formed
from two aldoses, for example lactose or maltose, are
preferably esterified by the phosphatidyl group by way
of the hydroxy group located in the 6-position of -the
pyranosyl radical in question. Disaccharides formed
from an aldose and a ketose, Eor exa~ple saccharose,
are prefera~ly esterified by the phosphatidyl group by
w~y of the hydroxy group located in the 5-position of
,, , j, .

~z~6~a6
- 29 -
~he pyranosyl radical or the hydroxy group located in
the l-position of the furanosyl radical.
A carbohydrate radical R4 having from 5 to 12
carbon atoms is also a derivatised mono- or di-
saccharide radical in which, for example, the aldehyde
group and/or one or two terminal hydroxy groups are
oxidised to carboxy groups, for example 3-gluconic, D-
glucaric or ~-glucoronic acid radicals which are
preferably present in the form of cyclic lactone
radicals. It is likewise possible in a derivatised
~ono- or di-saccharide radical for aldehyde or keto
groups to be reduced to hydroxy groups, :Eor example
inositol, sorbitol or D-mannitol, or for hydroxy groups
to be replaced by hydrogen, for example desoxy-sugars,
for example 2-desoxy-~-ribose, L-rha~nose or L-fucose,
or by amino groups, for example an amino-sugars, for
example D-glucosamine or D-galactosamine.
A carbohydrate radical R4 can also be a cleavage
product formed by the reaction of one of the mentioned
mono- or di-saccharides with a strong oxidising agent,
for exa~ple periodic acid.
A steroid radical R4 is, for example, a sterol
radical that is esterified by the phosphatidyl group by
way of the hydroxy group located in the 3-position of
the steroid nucleus.
A sterol radical is~ or example, the lanosterol,
sitosterol, coprostanol, cholestanol, ~lycocholic acid,
ergosterol or stigmasterol radicall preferably the
cholesterol radical.
If R4 represents a steroid radical, R1 and
R2 are preferably hydroxy and R3 i.s hydrogen.
Phospholipids of the formula 5 can be in the form
of free acids or in the form of salts. Salts are
formed by reaction of the free acid of the for~ula II
with a base, for example a dilute, aqueous solution of

~Z~6~
- 30 -
an alkali metal hydroxide, for example lithium, sodium
or po~assium hydroxide, ~agnesium or calciu~ hydroxide,
a dilute aqueous a~monia solution or an aqueous
solution of an amine, ~or example a mono-, di- or tri-
lower alkyla~ine, for example ethyl-, diethyl- or
triethyl-amine, 2-hydroxy2thyl-tri-C1-C4-alkyl-
amine, or example choline, and a basic amino acid, for
example lysine or arginine.
A ~hospholipid of the formula 5 has especially two
acyloxy radicals Rl and R21 for example alkanoyloxy
or alkenoyloxy, for exa~ple lauroyloxy, myristoyloxy,
palmitoyloxy, stearoyloxy, arachinoyloxy, oleoyloxy,
linoyloxy or linoleoyloxy, and is, for example, natural
lecithin (R3 = hydrogen, R4 = 2-trimethylammonium
ethyl) or cephalin (R3 = hydrogen, R4 = 2-ammoniu~
ethyl) having different acyloxy radicals R1 and R2,
for example egg lecithin or egg cephalin or lecithin or
cephalin from soya beans, synthetic lecithin or
cephalin having different or identical acyloxy radicals
R1 and R2, for example 1-palmitoyl-2-oleoyl
lecithin or cephalin or dipalmitoyl, distearoyl,
diarachinoyl, dioleoyl, dilinoyl or dilinoleoyl
lecithin or cephalin, natural phosphatidyl serine (R3
= hydrogen, R4 = 2-amino-2-carboxyethyl) having
different acyloxy ra~dicals R1 and R2, for example
phosphatidyl serine from bovine brain, synthetic
phosphatidyl serine having different or identical
acyloxy radicals R1 and R2, for example dioleoyl-,
dimyristoyl- or dipalmitoyl-phosphatidyl serine, or
natural phosphatidic acid (R3 and R4 = hydrogen)
having different acyloxy radicals R1 and R2.
~ phospholipid of the for~ula 5 is also a
phospholipid in which R1 and R2 represent two
identical alkoxy radicals, for exa~ple n-tetradecyloxy
or n-hexa~ecyloxy (synthetic di-tetradecyl or dihexa-

~ Z~6~6
- 31 -
decyl lecithin or cephalin), R1 represents alk~nyl
and R2 represents acyloxy, for example myristoyloxy
or p~lmitoyloxy (plasmalogen, ~3 = hydrogen, R4 =
2-trimethylammonium ethyl), R1 represents acyloxy and
R2 represents hydroxy, (natural or synthetic
lysolecithin or lysocephalin, for example 1-myristoyl-
or 1-palmitoyl-lyso-lecithin or -cephalin, natural or
synthetic lysophosphatidyl serine, ~3 = hydrogen,
R4 - 2-amino-2-carboxyethyl, or example lysophos-
phatidyl serine from bovine brain or 1-myristoyl- or
1-palmitoyl-lysophosphatidyl serine, synthetic
lysophosphatidyl glycerine, R3 = hydrogen, R4 -
C~20H-CHOH-C~2-, natural or synthetic lysophospha-t-
idic acid, R3 = hydrogen, R4 = hydrogen, for
example egg lysophosphatidic acid or 1-lauroyl-, 1-
myristoyl- or 1-palmitoyl-lysophosphatidic acid).
A lipid that is analogous to a phospholipid and
can be homogeneously mixed with the amphiphatic
compound (I) having biological activity instead of the
phospholipid (Il) is, for example, a lysolecithin
analogue, for example 1-lauroyl-1,3-propanediol-3-
phosphoryl choline, a monoglyceride, for example
monoolein or monomyristin, a cerebroside, a ganglioside
or a glyceride that does not contain a free or
esterified phosphoryl or phosphonyl group in the 3-
position, for example a diacylglyceride or 1-alkenyl-1-
hydroxy-2-acylglyceride having the mentioned acyl or
alkenyl groups in which the 3-hydroxy group is
etherified by one of the mentioned carbohydrate
radicals, for example a galactosyl radical, for example
monogalactosyl glycerine.
Together with the amphiphatic compound (I) having
biological activity, the phospholipid (II) or the
analogous lipid, it is also possible to add to the
homogeneous mixture neutral lipids that are contained

- 32 -
in cell membranes and are soluble only in non-polar,
organic solvents, for example in chloroform.
~ uch neutral lipids are, for example, steroids,
for example oestradiol, or sterols, for example
cholesterol, ~-sitosterol, desmosterol, 7-keto-
cholesterol or 3-cholestanol, ~at-soluble vitamins, for
example vitamins ~1 and ~2 or vita~in E, K
~2~ ~2 or ~3
The lipids ~entioned hereinbefore and hereinafter
having a chiral carbon atom can be present both in the
form of racemic mixtures and in the form of optically
pure enantio-mers in the pharmaceutical compositions
that can be manufactured according to t~e invention.
The invention preferably relates to a process for
the manufacture of pharmaceutical compositions in the
form of aqueous dispersions containing unilamellar
liposomes comprising (I) acid addition salts of
antidepressants of the formula
IR2 -NH-Rl
.~'\,/i\/'~
!~ ~1! n 1~1! ~J (1.8)
in which R1 represents lower alkyl, for example
methyl, ~2 represents lower alkylene, for example
methylene, ethylene or 1,3-propylene, or hydroxy-lower
alkylene, or example 2~hydroxy-1,3-propylene, and n
represents O or 2; acid addition salts of anti-
depressants of the formula

~LZ~64~
~o \ > \ ~ \ ./ 2
11 1 11 (19)
~. / \ A / ~ . /
in which Rl represents lower alkyl, for example
methyl, ~ represents the group N-Rl, oxygen or
sulphur, and R2 represents hydrogen or cyano; acid
addition salts of antidepressants of the formula
~. / A \ ~ . \
Rl
in which Rl represents lower alkylamino-lower alkyl,
~or example 3-methylamino-n-propyl, di-lower alkyl-
amino-lower alkyl, for example 3-dimethylamino-n-
propyl, or 3-(4-(2-hydroxyethyl)-piperazin-1-yl)-n-
propyl and A represents ethylene or vinylene; acid
addition salts of psychoanaleptics, anoretics or
a~renergics having a phenylaminopropane or
cyclohexylaminopropane structure, for example
amphetamine, methamphetamine, benzphetamine,
propylhexedrine, prolintan, fencamfin, methylphenidate,
pipradrol or phenmetrazine; acid addition salts of

~2~
- 34 -
spasmolytics, such as adiphenine; acid addition salts
of sympathomimetics of the formula 1.5, for example
epinephrine, norepinephrine, dopamine, nordefrin,
ethylnorepinephrine, isoprenaline, isoethorine,
metaproterenol, orciprenaline, ~etaraminol,
phenylephrine, hydroxyamphetamine, methoxyphenamine,
ephedrine, norephedrine, pholedrine, tyramine,
nor~enefrin or octopamine; ~-receptor blockers of the
formula 1.6, for example acebutolol, atenolol,
toliprolol, alprenolol, oxprenolol, bunitrolol,
bupranolol, talinolol, phenbutolol, bufetolol or
varbian (R,S-form and S-form); compounds having an
action on peripheral noradrenaline storers, for example
reserpine, rescinnamine or syringopine; glucocorticoids
that are esterified in the 21-position by an amino
acid, for example prednisolone diethylaminoacetate, or
analgesically active phenylacetic acid salts, for
example the sodium salts of diclofenac and pirprofen,
and (II) a phospholipid of the formula 5 having two
acyloxy radicals R1 and R2, for example lauroyloxy~
myristoyloxy, palmitoyloxy, stearoyloxy, arachinoyloxy,
oleoyloxy, linoyloxy or linoleoyloxy, for example
natural lecithin (R3 = hydrogen, R4 = 2-trimethyl-
ammonium ethyl) or natural cephalin (R3 - hydrogen,
R4 = 2-ammonium ethyl) having different acyloxy
radicals R1 and R2, for example egg lecithin or
cephalin, or lecithin or cephalin from soya beans,
synthetic lecithin or cephalin having different or
identical acyloxy radicals R1 and R2, for example 1-
palmitoyl-2-oleoyl lecithin or cephalin, or
dipalmitoyl, distearoyl, diarachinoyl, dioleoyl,
dilinoyl or dilinoleoyl lecithin or cephalin, natural
phosphatidyl serine (R3 = hydrogen, R4 = 2-amino-2-
carboxyethyl) having different acyloxy radicals R1
and R2, for example phosphatidyl serine from bovine

L6~gl6
- 35 -
brain, synthetic phosphatidyl serine havin~ different
or identical acyloxy radicals R1 and R2, for
example dioleoyl-, dimyristoyl- or dipalmitoyl-
phosphatidyl serine, or natural phosphatidic acid (R3
and R~ = hydrogen) having different acyloxy radicals
~1 and R2.
The invention relates especially to a process for
the manufacture of pharmaceutical compositions in the
form of aqueous dispersions containing unila~ellar
liposomes comprising (I) acid addition salts of anti-
depressants of the formula 1.8, for example 1-(2R-2-
hydroxy-3-methylaminopropyl)-dibenzo[b,e]bicyclo-
[2.2.2]octadiene, and the 2RIS-isomeric mixture~
maprotiline, benzoctamine acid addition salts of anti-
depressants of the formula 1.9, for example 3-methyl-
dibenz[2,3:6,7]oxepino[4,5-d]azepine hydrochloride,
7-cyano-4-methyl-2~3~4~5-tetrahydro~ -dibenzo[2~3:6~7]
thiepino[4,5-d]azepine ethanesulphonate, 3,10-dimethyl-
1,2,3,4,5,10-hexahydrodibenzo[b,f]azepino[4,5]a2epine
maleate; acid addition salts of antidepressants of the
formula 1.10, for example clomipramine, opipramol,
~esipramine or imipramine or i!nipramine N-oxide; acid
addition salts of sympathomimetics of the formula 1.5,
for example ephedrine or norephedrine; asid addition
salts of ~-receptor blockers of the formula 1.5, for
example 1-isopropylamino-3-[4-(2-methylthioethoxy)-
phenoxy]-propan-2-ol, 1-isopropylamino-3-(2-pyrrol-1
ylphenoxy)-propan-2-ol, oxprenolol or prenalterol;
spasmolytics, such as adiphenine, compounds havin~ an
action on peripheral noradrenaline storers, for
example reserpine, glucocorticoids that are esterified
in the 21-position by an amino acid, for example
prednisolone diethylaminoacetate; analgesically active
phenylacetic acid salts, ~or example the sodium salts
of diclofenac and pirprofen, and (Il) a phospholipid of

6~
- 36 -
the formula 5, for example natural lecithin or
cephalin, synthetic 1-palmitoyl-2-oleoyl lecithin or
cephalin, dipalmitoyl, ~istearoyl, diarachinoyl,
dioleoyl, dilinoyl or dilinoleoyl lecithin or cephalin,
natural phosphatidyl serine, synthetic 1-palmitoyl-2-
oleoylphosphatidyl serine, dimyristoyl- or dipalmitoyl-
phosphatidyl serine or natural phosphatidic acid.
The manufacture of the homogeneous mixture of
co~ponents can be effected in a manner known per se
by film or lyophilisate formation. In film formation,
the lipid, for example soya lecithin, and the biolo-
gically active compound, or example a phar~aceutical
active ingredient, for example a sodiu~ salt of
diclofenac, are dissolved in an organic solvent. By
removing the organic solvent, most advantageously in
vacuo, preferably under a high vacuum, or by sweeping
away with inert gas, for example ni-trogen, a thin film
of the components is prepared.
The choice of suitable solvents for the
manufacture of the film i5 dependent upon the
solubility of the lipid components and the inclusion
compounds. Suitable solvents for the manufacture of
the homogeneous mixture by film formation are, for
example, unsubstituted or substituted, for example
halogenated, aliphatic or cycloaliphatic hydrocarbons,
for example n-hexane, cyclohexane, methylene chloride
or chloroform, a~cohols, for example ~nethanol or
ethanol, lower alkanecarboxylic acid esters, for
example ethyl acetate, or ethers, for example diethyl
ether, or mixtures of these solvents. The solvent is
removed in vacuo, preferably under a high vacuum,
or by sweeping away with inert gas, for example
nitrogen.
The lyophilisate formation is effected by
lyophilisation of a solution of the active ingredient

4~
to be encapsulated and the lipid components in the
manner described in DE-~ 2 818 655. Suitable solvents
are solid during freeze-drying, for example at -the
temperature of the methanol, ethanol or acetone drying
mixture, together with the lipid components and the
inclusion compounds, and are, for example, organic
solvents having a melting point higher than 0C, for
example glacial acetic acid, benzene or dioxan,
especially tert.-butanol.
~ homogeneous mixture can also be prepared by
spray-drying a solution of a cationic tenside,
phospholipid and an inclusion compound in an organic
solvent. The homogeneous mixture is obtained in the
form of a powder.
In the homogeneous mixture, the approximate molar
ratio of biologically active compound to lipid is
approximately from 0.1 to approximately 2:1, preferably
from approximately 0.8 to approximately 1.2:1.
Dispersion is effected, for example, by shaking
(for example vortex mixer) or stirring the aqueous
phase which contains the previously prepare~
homogeneous mixture~ The formation of unilamellar
liposomes ~SUL) and (LUL) takes place spontaneously
(spontaneous vesiculation), that is to say without the
additional supply of external energy and at high speed.
A~proximately from 0.1 to 50% by weight, preferably
approximately from 2 to 20% by weight (in relation to
the total weight of the aqueous dispersion) of the
homogeneous mixture can be dispersed in the aqueous
phase.
Aqueous dispersions having a pH value greater than
approximately 8 are neutralised af-ter the dispersion
operation, for example to the physiological pH value of
7.2. The neutralisation is necessary in order to avoid
possible destruction of the active ingredient and/or

~6~
- 38 -
liposomes under basic conditions and in order to ensure
physiological tolerability of the administrable aqueous
dispersion with the liposome mixture. Neutralisation
is effected, for example, with a physiologically
tolerable, dilute aqueous solution of an acid or a
buffer solution having a pH value of from 7 to 8.
Physiologically tolerable acids are, for exa~ple,
dilute aquQous mineral acids, for example dilute
hydrochloric acid, sulphuric acid or phosphoric acid,
or dilute organic acids, for example lower
alkanecarboxylic acids, for example acetic acid.
Aqueous dispersions with amphiphatic compounds o
the formula 1 can react acidically. These are
neutralised by the addition o dilute aqueous bases,
or example dilute aqueous sodium or potassium
hydroxide solution or a buffer solution having a pH
value o rom 7 to 8, especially pH 7.2.
~ queous dispersions with amphiphatic compounds of
the ormulae 2 and 4 can react basically. These are
neutralised by the addition o a suitable physlolo-
gically tolerable acid, for example a weak organic
acid, for example acetic acid, or a dilute aqueous
mineral acid, or example dilute aqueous sulphuric
acid. Neutralisation is carried out with simultaneous
monitoring o the pH value.
The operations are advantageously carried out at
room temperature or alternatively at higher
temperatures, ~or example up to approximatsly 60C,
and while stirring or shaking. I~ the sensitivity o~
the active ingredient to be encapsulated de~ands, the
process is carried out while cooling and optionally
under an inert gas at~osphere, or example a nitrogen
or argon atmosphere.
The size o the unilamellar liposomes formed
depends, inter a _ , on the structure of the active

~6gL~
- 39 -
ingredient and the lipid component, the mixing ratio of
the components and the concentration of these
components in the aqueous dispersion. Thus, for
example, by increasing or reducing the concentration of
the lipid component it is possible to produce aqueous
phases having a high content of small or large
unilamellar liposomes. In addition to SUL there are
also formed large unilamellar liposomes (LUL-diameter
up to 5.0 x 10~6m) and, possibly, multilamellar
liposomes.
The separation of the SUL from the LUL and any
multilamellar liposomes formed as a secondary product,
if desired, is effected by means of conventional
separation methods, for example sedimentation of the
LUL in an ultracentrifuge, gel filtration or extrusion
through straight-pored filters. For example, on
centrifuging, for example for from 5 to 30 minutes in a
rotating field giving rise to an inertial force
equivalent to a gravitational field of 5000-40 000 g,
LUL are deposited, whilst the SUL remain dispersed and
can be decanted off. After repeated centrifugation,
complete separation of the LUL from the SUL is
obtained.
It is also possible to separate off all the
liposomes in the aqueous phase having a diameter
greater than 6.0 x 10 8m, for example LUL or multi-
lamellar liposomes, as well as non-encapsulated active
ingredients and excess dispersed lipids that are
present in high-molecular-weight aggregates, by gel
filtration, for example with Sepharose or Sephacryl as
carriers and thus to obtain an aqueous phase having a
fraction SUL of relatively uniform size.
By extrusion through straight-pored filters, for
example membrane filters of the Nucleopore ~ type
having a pore diameter of approximately 5.0 x 10 8m,

~z~
- 40 -
at a pressure of approximately from 0.1 to 1.5 bar, and
a filtration rate of approximately 20 ml/h, it is
possible to obtain a particularly uniform size
distribution of the unilamellar liposomes. The
filtrate can subsequently be enriched with unilamellar
liposomes by way of an ultrafilter, for example Amicon
U?~l 1 0 ~.
The resulting liposomes are suitable ~or
administration to patients and are stable in aqueous
phase for a relatively long period (up to several days
or weeks). Aqueous dispersions with the unila~ellar
liposomes that can be manufactured according to the
invention can be made suitable for storage by the
addition of stabilisers, for example mannitol or
lactose.
The completed formation of small unila~ellar
liposomes (SUL) and their content in the aqueous phase
can be detected in a manner known per se using
various physical measuring methods, ~or example with
freeze-fracture samples and thin sections in an
electron microscope or by X-ray defraction, by dynamic
light scattering, by mass determination of the filtrate
in an analytical ultracentrifuge and, especially,
by spectroscopy, for example in the nuclear
resonance spectrum (1H, 13C and 31p). For
example, sharp signals having a narrow line width in
the nuclear resonance spectrum indicate the completed
formation of unilamellar liposomes of a diameter less
than approximately 1000 ~. Sharp signals at ~ approxi-
mately 0.89 ppm ~-CH3), S approximately 1.28 ppm
(-CH2-) and S approximately 3.23 ppm (-N(CH3)3)
are characteristic, for example, of small unilamellar
liposomes (vesicles) obtained according to the process
with phosphatidyl choline (lecithin) as co~ponent. In
the nuclear resonance spectrum such signals are typical

2~;4~6
of unila~ellar liposomes and differ markedly from
signals caused by mixed micelles and larye unilamellar
and multila~ellar liposomes. Large unilamellar and
multilamellar liposo~es with lecithin as component
cause a broad coherent methyl and methylene signal of
lesser intensity. A methyl signal of ~ approximately
0.89 ppm is characteristic of mixed micelles with
lecithin as component, which signal is resolved to a
tripiet and has a considerably smaller line width than
the methyl signal (singlet, likewise at S approximately
0.89 ppm) that originates from unilamellar liposomes.
~ u~ous dispersions with the liposomes obtainable
according to the invention and encapsula-ted active
in~redients are administration systems which,
optionally after concentration or isolation of the
liposomes, for example by ultracentrifugation, are
suitable for therapeutic purposes for oral (p.o.),
parenteral (i.v., i.m. or i.p.) or topical admini-
stration.
In the case of oral administration, administration
systems based on liposomes can improve the resorption
o an active ingredient.
For oral administration, the liposome-containing
aqueous dispersion can be mixed with pharmaceutically
~cceptable diluents or carriers or with customary
additives, for example colourings or flavourings, or
can be used in the form of a syrup or in the form of
capsules.
For parenteral administration, the aqueous
dispersion or the enriched liposomes can be suspended
in a suitable carrier liquid, for example sterile,
isotonic common salt or glucose solution, optionally
buffered to pH 7.2.
For topical administration the liposome-containing
aqueous dispersion can be mixed with customary thick-

~2~
- 42 -
eners, for example hydroxypropylcellulose, suitable
preservatives, antioxidants and perfumes, and can be
used in the form of a lotion or a gel for applica~ion
to the skin or mucous membranes.
The dosage of active ingredient to be administered
is generally the highest and lowest amount prescribed,
for example in the Deutsches Arzneimittelbuch (D~B)
[German Pharmacopoeia], for the active ingredient in
question for the paxticular form of administration, the
age of the patient and the health of the patient.
Aqueous dispersions with liposomes that can be
manufactured according to the invention also have the
advantage, however, that active ingredients
administered in smaller doses can pass to the
receptors and can there bring about a therapeutic
effect, or, on administration of higher doses,
undesirable side effects can be avoidedO
The active ingredients mentioned hereinbefore are
known. Active ingredients of which the generic names
are given are commercially available. The mentioned
lipids, especially the phospholipids of the formula 5,
are known and some are commercially available.
The following Examples illustrate the invention
but do limit the invention. Temperatures are given in
degrees Centigrade and chemical shifts in the NMR
spectrum are given in ppm of standard tetramethyl-
silane. Unless otherwise indicated the signals are
singlets. Sharp singlet signals at 1.26 - 1.32 ppm
are characteristic of the methylene groups of the
phospholipid of the formula 5 which is present in the
aqueous dispersion in the form of small unilamellar
liposomes. Phospholipids of the formula 5, which are
present in the aqueous dispersion in the form of large
unilamellar or multilamellar liposomes, have broad
signals from approximately 0~5 to approximately 1.8

64~
- 43 -
ppm. From the ratio of -the intensities of the singlet
signals of the methylene groups of the lipid and the
standard sodium acetate it is possible to calculate the
yield of small unilamellar liposomes (S~L). Sterile
water that has been washed free of particles is used
for preparing the aqueous dispersions.

- 4~ -
~xample 1
1.1 50 mg (approximately 0.066 mmol) oE soya
lecithin are weighed into a 15 ml phial, and a solution
of 20.33 mg (0.066 mmol) of 1-isopropylamino-3-(2-
pyrrol-1-ylphenoxy)-propan-2-ol hydrochloride in 3 ml
of a 1:1 methanol/chloroform mixture is added
thereto. ~fter the lecithin has been dissolved in the
organic phase, the phial, in a horizontal position, is
set rapidly in rotation until a film of liquid adheres
to the glass wall. The solvent is removed by sweeping
it away with nitrogen and the lipid film that has
formed is dried under a high vacuum for several hours.
1.2 1.5 ml of water or (if it is intended to record
an 1H-NMR spectrum) D2O are then added to this
lipid film and the phial is shaken for several minutes,
optionally mechanically and at high speed (vortex
mixer). A slightly opalescent, aqueous dispersion is
obtained.
The completed formation of small, unilamellar
liposomes (SUL) can be detected in the 1H-NMR
spectrum (360 MHz) inter alia by a sharp singlet
signal at 0.53 ppm which is characteristic of the
methyl groups of the lipid soya lecithin. The spectrum
also shows in the range of from 0.53 to 1.53 ppm a
broad signal of lesser intensity, which is assigned to
the methyl and methylene groups of the soya lecithin
contained in large unilamellar and multilamellar
liposomes. In addition to other signalsr the doublet
at 1.26l which is assigned to the -CH(CH3)2 group
of the active ingredient, is characteristic. Yield oE
SUL: 23.4%.
The unilamellar liposomes formed can be observed
in an electron microscope. The liposome dispersion is

~2~G~
- 45 -
first subjected ~o the customary freeze-fracture
method. There are chiefly two "populations" of
unilamellar liposomes present which differ in their
average size:
1. Small unilamellar liposomes (SUL) having a
diameter of approximately 2.0-6.0 x 10~3m, and
2. Large unilamellar liposomes (LUL) having a
diameter of approximately 1.0 x 10 7 - 1.0 x 10~6m~
Example 2
In a manner analogous to that described in Example
1.1, a lipid film is prepared from S0 mg (approximately
0.066 mmol) of soya lecithin and an equimolar amount of
the following ac~ive ingredients, and the film is
dispersed analogously to Example 1.2 in 2.5 ml of wa~er
or D2O. The 1H-NMR spectra show sharp singlets for
the methyl and methylene groups of the lecithin present
in the form of SUL and a broad signal of lesser
intensity for the methyl and methylene groups of the
lecithin present in the form of LUL and multilamellar
liposomes. In addition, the signals characteristic of
the particular active ingredient can be detected.
2.1 21.15 mg of 1-(2R-2-hydroxy-3-methylaminopropyl)-
dibenzo[b,e]bicyclo[2.2.2]octadiene hydrochloride (NMR:
3.30 -NHCH3), yield SUL: 12.4%.
2.2 21.15 mg of 1-(2R,S-2-hydroxy-3-methylamino-
propyl)-dibenzo[b,e]bicyclo[2.2.2]octadiene hydro-
chloride (NMR: 3.26 -NHCH3), yield SUL: 22.0%.
2.3 20.06 mg of 3-methyldibenzo[2,3:6,7]oxepino-

~2~ L6
- 4~ -
[4,5-d]azepine hydrochloride (NMR: 3.19 -NCH3),
yield SUL: 26%.
2.4 25.48 mg of 2,3,4,5-tetrahydro-3-methyl-lH-
dibenzo[2,3:6,7]thiepino[4,5-d)azepine-7-cyanomethane-
sulphonate (NMR: 3.14 -NCH3), yield SUL: 29.5~.
~.5 26.80 mg of 3,10-dimethyl-1,2,3,4,5 ! 10-hexahydro-
dibenzo[b,f]azepino[4,5]azepine maleate (NMR: 1.38
CH(CH3)2-dublet, 2.19 -SCH3), yield
SUL: 25%.
2.6 46.99 mg of 1-isopropylamino-3-[4-(2-methylthio-
ethoxy)-phenoxy]-propan-2-ol fumarate (NMR: 1.38
-CH(CH3)2-dublet~ 2.19 -SCH3), yield
SUL: 25%.
2.7 20.262 mg of N,N-dimethyl-5-phenyl-1,2,4-triazolo-
[1,5-a]quinoxalin-2-ylmethylamine hydrochloride (NMR:
3.04 -NCH3, 2.91 -N(CH3)2), yield SUL: 21.2%.
~.8 21.12 mg of clomipramine hydrochloride (NMR: 3.20
-N(CH3)2), yield SUL: 29%.
2.9 13.21 mg of ephedrine hydrochloride (NMR: 2.77
-NHCH3), yield SUL: 18~.
2.10 26.33 mg of opipramol (NMR: 7.10 -CH=CH-multi-
plet), yield SUL: 26%.
2.11 20.65 mg of maprotiline hydrochloride (NMR: 3~17
-NHCH3), yield SUL: 15.1%.
2.12 12.38 mg of phenylpropanolamine hydrochloride
(norephedrine hydrochloride, NMR: 1 .19 -NCH3), yield

~L2gL6~
- 47 -
SUL: 10.8~.
2.13 42.8t mg of oxprenolol succinate (MMR: 1.30
-CH3-doublet), yield SUL: 24%.
2.14 19.92 mg of desipramine hydrochoride (NMR:
6.77 - 7.44, mul~iplet-arom. ~), yield SUL: 17.7~.
2.15 20.91 mg of phentolamine hydrochloride (N~R:
2-30 -C6H5-CH3), yield SUL: 12.2%.
2.16 18.80 mg of benzobutamine hydrochloride (NMR:
3.67 -NCH3), yield SUL: 10.2%.
2.17 20.84 mg of imipramine hydrochloride (NMR: 3.07
-NCH3), yield SUL: 24.1~.
2.18 22.96 mg oE adiphenine hydrochloride (NMR: 2.00
-CQOCH2-), yield SUL: 56%.
2.19 30.08 mg of oxprenolol hydrochloride (NMR: 1.33
-CH3-doublet), yield SUL: 16%.
2.20 17.19 mg of prenalterol hydrochloride (NMR: 1.33
-CH3-doublet , 6.87 arom. H-multiplet), yield
SUL: 16~.
2.21 18.67 mg of diclofenac sodium (NMR: 3.00
-CH2-), yield SUL: 16%.
2.22 17.74 mg of methylphenidate hydrochloride (NMR:
3.73 -COOCH3), yield SUL: 10.3%.

~2~
- 4~ -
Example 3
3.1 23.26 mg (approximately 0.066 mmol) of cefroxadin
are dissolved in 5 ml of a 2:1 dioxan/methanol mixture
in the presence of slight traces of water. 50 mg
(approximately 0.066 mmol) of soya lecithin are
dissolved in the clear solution. The solvent is
removed in vacuo at 50. The lipid film that has
formed is dried under a high vacuum for several ho~rs.
3.2 2.5 ml of water or (if it is intended to record an
1~-NMR spectrum) D2O are then added to this film
and the whole is shaken for several minutes, optionally
mechanically and at high speed. After the addition of
a drop of a 1% solution oE bromothymol blue in D2O,
titra~ion is carried out with a few drops of a lN NaOH
or NaOD/D2O solution to produce a colour change from
yellow ~o blue (pH approximately 9-10). After several
minutes mechanical stirring, the dispersion is
neutralised with lN H2SO4 or D2SO4/D2O
solution (colour change from blue to yellow). A
slightly opalescent, aqueous dispersion is obtained.
In the NMR spectrum, in addition to the methyl and
methylene signals that are characteristic of the lipid,
and other signals, a singlet can be detected at
3.73 ppm which is assigned to the OCH3 group of
cefroxadin. Yield SUL: 13.2%.
~xample 4
4.1 50 mg (approximately 0.066 mmol) of soya lecithin
are weighed into a 15 ml phial, and a solution of
16.53 mg (0.066 mmol) of pirprofen in 3 ml of a 1:1
methanol/chloroform mixture is added thereto. After
the lecithin has been dissolved in the organic phase,

2~
_ a~g _
~he phial is set rapidly in rotation until a film of
liquid adheres to the glass wall. The solvent is
removed by sweeping it away with nitrogen and the lipid
film that has formed is dried under a high vacuum for
several hours.
4.2 2.5 ml of water or (if it is intended to record an
1H-NMR spectrum) D2O are then added to this lipid
film and the whole is shaken, optionally mechanically,
or several minutes. After the addition of a drop of
bromothymol blue in D2O, titration is carried out
with a few drops of a 1N NaOD/D2O solution to produce
a colour change from yellow to blue (pH approximately
9-10). ~fter several minutes' mechanical stirring,
the dispersion is neutralised with lN H2SO4 or
D2SO4~D2O solution ~colour change from blue to
yellow). A slightly opalescent, aqueous dispersion is
obtained. In the NMR spectrum, in addition t~ the
methyl and methylene signals that are characteristic of
the phospholipid and in addition to other signals, a
broad singlet can be detected at 6.04 ppm which is
assigned to the vinyl protons in the pirprofen. Yield
SUL: approximately 11.6%.
Example 5
5.1 In a manner analogous to that described in Example
4.1~ a film of liquid is prepared from 50 mg (approxi-
mately 0.066 mmol) of soya lecithin and 40.17 mg (n . 066
mmol) of reserpine and is subsequently dried under a
high vacuum.
5.2 25 ml of water or (if it is intended to record an
~ NMR spectrum) D2O are then added to this film
and the whole is shaken for several minutes, optionally
mechanically and a~ high speed. After the addition of

- 5O -
a drop of a 0.5% solution of bromophenol blue in D2O,
titration is carried out with a few drops of a 1N
H2SO4 or D2SO~/D2O solution to produce a
colour change from blue to yellow (pH approximately 3).
~fter several minutes' mechanical stirring, the
dispersion is neutralised with lN NaOH or NaOD/D2O
solution. A slightly opalescent, aqueous phase is
obtained. In the NMR spectrum, in addition to the
methyl and methylene signals characteristic of the
lipid and other signals, a singlet can be detected at
3.81 ppm which is assigned to the -OCH3 groups at the
phenyl ring of the reserpine.
Example 6
6.1 In a manner analogous to that described in Example
4.1, a film of liquid is prepared from 50 mg (approxi-
mately 0.066 mmol) of soya lecithin and 31.26 mg
(approximately 0.066 mmol) of prednisolone diethyl-
aminoacetate and is then dried under a high vacuum.
6.2 ~n aqueous dispersion having unilamellar liposomes
is then prepared from this film analogously to Example
5.1. In the NMR spectrum, in addition to the methyl
and methylene signals characteristic of ~he lipid and
other signals, a singlet can be detected at 7.66 ppm
which is assigned to the vinylic proton of the
prednisolone nucleus that is in the ~-position to the
carbonyl group.
~xample 7
-
7.1 2.9 g ~3.88 mmol) of soya lecithin are dissolved
in 20 ml o~ tert.-butanol at approximately 50. At
this temperature, while stirring, 2 ml of water are

~L2~6446
added dropwise and then 2 g (3.88 mmol) of beta-
methasone disodium phosphate are dissolved in the
solution. The clear solutlon is frozen at -30 and
freeze-dried at this temperature.
7.2 2.5 ml of water are added to the resulting
lyophilisate and the whole is mechanically shaken for 5
minutes. ~ slightly opalescent, aqueous dispersion
having unilamellar liposomes is obtained. In the
H-NMR spectrum it is possible to detect the
methylene and methyl signals of the lipid and, inter
alia, a doublet at 7.49 (J = 9 Hz, 1-H atom at the
steroid nucleus), doublet at 6.38 (J = 9 H~, 2-H atom)
and a singlet at 6.19 (4-H atom). Yield SUL : 44%.
7.3 The resulting aqueous dispersion is adjusted to pH
7.4 by the addition of sterile 0. lN hydrochloric acid.
After introduction into a stirred ultrafiltration cell
(~micon ~ , which instead of the ultrafilter is
provided with a straight-pored membrane filter of
polycarbonate (Nucleopore~ having a pore diameter of
0.05 ~m and which has been washed free of particles,
filtration is carried out under a slight excess
pressure of approximately from 0.1 to 1.~ bar and with
a constant supply of sterile-filtered buffer solution
according to Dulbecco (pH 7.4~ without Ca and Mg) at a
speed of 20 ml/h, until approximately 500 ml of
filtrate have been obtained. This filtrate is fed
continuously inko a stirred filtration cell equipped
with an ultrafilter, for example Amicon U 10 ~, and
concentrated to a volume of 30 ml. The concentrated
aqueous dispersion contains small, unilamellar
liposomes and, after the addition of a concentrate of
phosphate buffer according to Dulbecco (pH 7.4 without
Ca and Mg), can be introduced into ampoules and used

6~L6
- 52 -
for treatment tests.
7.4 In a manner analogous to that described in Example
7.3, it is possible to manufacture by membrane
filtration and subsequent ultrafiltration concentrated
aqueous dispersions containing small unilamellar
liposomes with the compositions indicated in Examples 1
to 6 and 8.
Example 8
8.1 In a manner analogous to that described in Example
7.1, a lyophilisate is manufactured from 3.21 g (4.22
mmol) of soya lecithin and 2 g (4.22 mmol) of
prednisolone diethylaminoacetateO
8.2 In a manner analogous to that described in Example
7.2, the resulting lyophilisate is dispersed in water,
and a slightly opalescent, aqueous dispersion having
unilamellar liposomes is obtained. In the 1H-NMR
spectrum it is possible to detect the methyl and
methylene signals of the lipid and, inter alia, a
broad signal at 6.31 (2-H atom at the steroid nucleus)
and a singlet at 6.06 (4-H atom). Yield SUL: 14.4~.
Example 9 (Anti-inflammatory steroid injection
~ preparation)
29 g of 1-palmitoyl-2-oleoyl lecithin are
dissolved in 450 ml of tert.-butanol at 50. ~hile
stirring, 20 ml of distilled water and 20 g of beta-
methasone disodium phosphate are added ~o this
solution. In a sterile room, the resulting solution is
filtered through a sterile filter (for example Acrodisc
0.2 ~m) into a sterile flask washed free of particles

~2~
- 53
and having a pipette metering attachment. 0.1 ml
portions of this solution (corresponding to 4 mg of
active ingredient) are introduced into washed, sterile
2 ml phials, lyophilised under sterile conditions and
sealed under dry nitrogen. The resulting dry
preparation is stable to s~orage. Before use, 1 ml of
sterile, phosphate-buffered (pH 7.4) common salt
solution is added to this dry preparation using a
sterile syringe and the phials are shaken for 1 minute
in a standardised laboratory shaker (vortex, Stage 6).
The resulting liposome dispersion is suitable for intra-
muscular, intra-articular, intradermal or intralesional
injection.
Example 10 (Steroid cream)
.
29 g of soya lecithin (Epikuron 200 ~ are dissolved
in 200 ml of tert.-butanol at 50. At this
temperature, while stirring, 20 ml of distilled water
and 20 mg of betamethasone disodium phosphate are
added. The solution is frozen, lyophilised and ground
at low temperature under a nitrogen atmosphere (dry).
The lyophilisate is stirred in a stirring vessel for a
period of 10 minutes in 5 kg of distilled water. In a
Moltomat an aqueous gel is prepared from 14.4 kg of
water, 300 g of Klucel and 200 g of sodium ascorbate
and customary perfumes and preservative additives in a
manner known per se, and the liposome mixture is
mixed in. The resulting cream is suitable for the
treatment of weeping dermatoses.
Example 11 (Antirheumatic agent for peroral
administration)
1 kg of soya lecithin (Epikuron 200 ~ is

~2~6a~
- 54 -
dissolved in 5 litres of ~ert.-butanol at 50. At
this temperature 250 ml of water and 250 g of
diclofenac sodium are added. The solution is
lyophilised and the lyophilisate is ~inely ground under
a nitrogen atmosphere (dry) in a pinned disk mill and
then mixed in a Turbula mixer with 2.5 kg of ground
lactose, 5 g of sodium ascorbate and flavour-
correctors. 750 mg portions of the pulverulent mixture
are sealed into composite foil bags tpolyethylene/
aluminium/paper). ~efore administration, ~he contents
of the bag are stirred in a glass of water (1 dl), a
liposome dispersion for drinking being formed.
~xample 12 (Eye drops against conjunctivitis)
20 g of 1-palmitoyl-2-oleoyl lecithin are
dissolved in 400 ml of tert.-butanol. 40 ml of
distilled water and 2 g of diclofenac sodium are added.
The solution is filtered in a sterile room through a
sterile filter (Eor example ~crodisc 0.2 ~m) into a
sterile flask washed free of particles and having a
pipette attachment. 1 ml portions of ~his solution
(corresponding to 50 mg of phospholipid) are introduced
into washed, sterile 50 ml phials, frozen at -70,
sterile-lyophilised and sealed under dry nitrogen. The
resulting dry preparation is stable to storage. ~efore
use, 2.5 ml of sterile~ phosphate-buffered common salt
solution (according to Dulbecco, Ca- and Mg-free, pH
7.4) are added to the dry preparation and the phials
are shaken vigorously for approximately 20 seconds.
The resulting suspension can be stored for 1 month in a
refrigerator if kept sealed. For treatment, 1 or 2
drops are applied to each eye daily.