CA1246446A - Process for the manufacture of pharmaceutical compositions containing unilamellar liposomes - Google Patents

Abstract

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.

Description

4~6 ~-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~

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

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 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~

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 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 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 \.

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~

R1~ CH - ~ ~;

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 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~

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~

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 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

~./ \./ ~. / \ ./ ~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~

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~

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 . \ / COOH
i1 ./ ~ NH

~ . ~ \ / (2.1) ~./ \ 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 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~

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 R O
13 ll Rl-CH2-C-CH2--P--R4 (5 ) 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), 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 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 ~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~

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 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 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~

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 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~

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~

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~

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~

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~

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~

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~

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~

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 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 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~

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~

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.

Claims (12)

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 (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-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 (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 (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) 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 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 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 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 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, 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 (1.1) in which R1, R2 and R3 have the following meanings:

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 (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 similar to morphine having an aliphatic or cycloaliphatic tertiary amino group, analgesics of the benzimidazole type of the formula (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-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 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 (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 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 (1.5) in which R1, R2, R3, R4 and R5 have the following meanings:

.beta.-receptor blockers of the formula:

in which R1, R2 and R3 have the following meanings:

.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 has been replaced by compounds of the reserpine type, tetracycline antibiotics of the formula (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 choleritics, analgesically active salts of substituted phenylacetic acids or 2-phenylpropionic acids, analgesically active anthranilic acid derivatives of the formula (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 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 (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 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-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-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).

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 (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 (1.9) in which R1 represents lower alkyl, A represents the group , oxygen or sulphur, and R2 represents hydrogen or cyano, acid addition salts of anti-depressants of the formula (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-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.-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-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.

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.