WO1997048381A1

WO1997048381A1 - Pharmaceutical preparation in the form of liposomes

Info

Publication number: WO1997048381A1
Application number: PCT/EP1997/003108
Authority: WO
Inventors: Georg Böck; Herbert Stricker; Bernd Disse
Original assignee: Boehringer Ingelheim Pharma Kg; Boehringer Ingelheim International Gmbh
Priority date: 1996-06-15
Filing date: 1997-06-14
Publication date: 1997-12-24
Also published as: EP0904058A1; DE19623950A1; JP2000513330A; CA2253285A1

Abstract

The invention relates to a pharmaceutical preparation in the form of liposomes, suitable for solubilisation of hardly soluble drugs, in particular of hardly soluble neurokinin antagonists, such as (+)-campher-3-carbonyl-(2S, 4R)-4-hydroxypyrolyl-(2S)-2-naphthylalanyl-(2-methoxyphenyl)piperazid or 1-methylindol-3-yl-carbonyl-[4(R)-hydroxy]-L-prolyl[3-(2-naphthyl)]-L-alanine-N-benzyl-N-methylamide.

Description

Pharmaceutical preparation in the form of liposomes

The present invention relates to a pharmaceutical preparation in the form of liposomes, suitable for the solubilization of poorly soluble drugs, in particular of poorly soluble neurokinin antagonists, such as. B. (+) - camphor-3-carbonyl- (2S, 4R) -4-hydroxypyrolyl (2S) -2-naphthylalanyl- (2-methoxyphenyl) piperazide [BIIC 1996 BS] or 1-methylindol-3-yl-carbonyl - [4 (R) - hydrxoy] -L-prolyl- [3- (2-naphthyl)] - L-alanine-N-benzyl-N-methylamide [FK 888],

Liposomes are generally understood to be spherical structures - with a diameter of 25 nm to several μm - from one or more concentric lipid bilayers with an aqueous interior. Such lipid vesicles can be produced by finely mechanical distribution of phospholipids (e.g. lecithin) in aqueous media. They are not only used as membrane models in biochemistry or molecular biology, but can also be used as carriers for drugs.

Numerous active substances are known from the prior art which are enclosed in liposomes or adsorbed on liposomes. Such liposomal systems are always preferred when the active ingredient is to be released over a longer period of time, undesired drug effects are to be reduced, the active ingredient is to be stabilized or liposomes are to be used as carrier-selective drug vehicles [P. Tyle and B.P. Ram, Targeted Therapeutic Systems, Marcel Dekker Inc., New York, 1990; G. Gregoriadis, Liposome Technology Vol. III, Targeted Drug Delvery and Biological Interaction, CRC Press Inc., Boca Raton, 1984]. Sufficiently water-soluble drugs have mostly been included in the above-mentioned liposomes [M.J. Ostro, Liposome - From Biophysics to Therapeutics, Marcel Dekker Inc., New York, 1987, G. Gregoriadis Liposome Technology Vol. II, Incorporation of Drugs, Proteins and Genetic Material, CRC Press Inc., Boca Raton 1984].

The aspect of drug solubilization by liposomes has recently become increasingly important. However, as part of initial research, the legalities of liposomal drug inclusion have so far remained relatively unexplored. The aim of drug solubilization in general is to To have drug in a mostly aqueous formulation in a molecularly disperse distribution. This formulation can then be administered by the known routes of application.

Drug preparations solubilized by liposomes should meet the following criteria:

The drug should be included in the liposome bilayer in molecularly dispersed form, provided that the ratio of the included drug to the amount of lipid used is as high as possible. Likewise, the drug liposomes should have a drug and size stability adapted to the intended use.

For a large number of application forms, it is essential to be able to produce sterile liposome preparations, for example by disinfection filtration with membrane filters with a pore diameter of 0.2 μm. Small liposomes, i.e. <200 nm liposome diameter should be aimed for in order to maintain sufficient stability of the liposomes during mechanical agitation. This is necessary, for example, when atomizing aqueous liposome preparations using pneumatic nozzle atomizers for inhalation application. To avoid embolic infusion incidents, it must be ensured that the size of the injected liposomes on the one hand does not exceed a critical value and that on the other hand the liposomes do not form aggregates of this critical size after intravenous administration. For use on patients in general, as well as for intravenous application in particular, only physiologically acceptable auxiliaries are to be used as solubilizers. The liposome components presented by way of example are suitable as constituents of the body, among other things, because they are non-toxic on the one hand and well tolerated on the other hand, and are broken down by the body without leaving any residue.

The object of the present invention is now to provide a drug formulation based on liposomes for the solubilization of poorly soluble drugs, in particular for neurokinin (tachykinin) antagonists, as described in the general formula, the preferred areas and in the exemplary embodiments of WO 95/30687 to be disclosed. - A primary object of the present invention is to provide a drug formulation based on liposomes for the solubilization of the active ingredients (+) -campher-3-carboπyl- (2S, 4R) -4-hydroxyprolyl- (2S) -2- naphthylalanyl- (2-methoxyphenyl) pιperazιd [BIIC 1996 BS] and 1-methylιndol-3-yl-carbonyl- [4 (R) -hydrxoy] -L-prolyl- [3- (2-naphthyl)] - L-alanιn -N-benzyl-N-methylamide [FK 888] (see Ann Drug Data Rep 15 (1993) 252). In addition, corticoids - such as flunisolide hemihydrate or beclomethasone dipropionate - can also be used to liposomally include compounds with the invention Establish proposed connections

BIIC 1996 is a non-selective neurokinin antagonist, which binds to the NK- | -, NK2- and NK3-Rezepor with affinities in the nanomolar range. Surprisingly, it was found that the liposome formulations according to the invention for the solubilization of pharmaceutical active ingredients described with the following Liposome components are produced, have special advantages. The drug-containing liposome preparations according to the invention thus solve the problem mentioned at the beginning and therefore represent a considerable advance in the solubilization of poorly water-soluble, lipophilic drugs

The liposome compositions according to the invention are distinguished, inter alia, by the fact that liposome-forming, amphiphilic auxiliaries, the physicochemical character of the hydrophilic molecular part of which is determined by glycerol or inositol, are particularly suitable for large amounts of poorly soluble medicinal substances - in particular the neurokine antagonists BIIC already mentioned 1996 BS and FK 888 - to be enclosed in liposomes

According to the invention, the liposome-forming auxiliaries correspond to the general formulas I and II in FIG. 1, in which R ^ and R2 in both general formulas independently of one another have a branched or unbranched alkyl radical of a natural, semisynthetically or fully synthetically producible fatty acid - saturated or unsaturated character Have 1 to 30 carbon atoms

Examples of saturated, unbranched fatty acids are formic acid, acetic acid, propionic acid, butyric acid, valenic acid, capronic acid, onanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, maric acid, stearic acid, stanic acid, paladic acid, palmitic acid, palmitic acid, palmitic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, paleodic acid Lignocennic, cerotic, melissic An example of saturated branched fatty acids are isobutyric acid, isovalane acid, tubercolostearic acid

Examples of monounsaturated, unbranched fatty acids are acrylic acid, crotonic acid, palmitoleic acid, oleic acid, erucic acid

Sorbic and linoleic acids are examples of double-saturated, unbranched fatty acids

Examples of triple-saturated unbranched fatty acids are linolenic and elaosteen acids

Arachidonic acid and clupanodonic acid are examples of a four- and five-fold unsaturated, unbranched fatty acid

Docosahexaenoic acid is an example of a six-fold unsaturated unbranched fatty acid

Phosphatidyl glycerols and phosphatidyl ion soles in the form of the free acids or their salts - in particular in the form of the alkali salts - are preferably used, and the sodium salts are very particularly preferably used

The following phosphatidylglycerols are particularly preferably used

Sodium salts of dimystoylphosphatidylglycerol (DMPG-Na), dipalmitoylphosphatidylglycerol (DPPG-Na) and distearoylphosphatidylglycerol (DSPG-Na)

The following compounds are particularly preferably used as phosphatidylinositols

Sodium salts of dimystoylphosphatidylinositol (DMPI-Na), dipalmitoylphosphatidylinositol (DPPI-Na) and disteraroylphosphatidylinositol (DSPI-Na)

1 shows the structural structure of phosphatidylglycerols and phosphatidyhnositols, in particular the structural formula of the sodium salt of phosphatidylglycerols and phosphatidyl inositols The liposome components according to the invention are characterized in that they are added to any further liposome components in proportions of greater than 0 mol% up to 100 mol%.

The liposomes produced by means of the liposome components according to the invention - in particular BIIC 1996-containing liposomes - have the following advantages.

1 The content of the pharmaceutically active component can be greatly increased by adding the liposome components according to the invention. For this reason, in order to achieve a high active ingredient concentration, a cost-intensive increase in the concentration of the other liposome components can be dispensed with

2 By varying the molar proportion of the liposome components according to the invention, the maximum inclusion of the drug can be controlled over a wide range

3 The liposome components according to the invention are indispensable for the simple production of active substance-containing liposomes in a size range <200 nm

4. The concentration of the solubilized drug can be controlled by varying the total lipid content

5 The liposomally enclosed drug - in particular the neurokinin antagonist BIIC 1996 BS - stabilizes the liposomes with regard to their growth in size.

6 Addition of cholesterol can stabilize liposomes with under-enclosed pharmaceuticals in terms of size growth

7. Both with mechanical agitation and with increasing storage time, drug-containing liposomes show no tendency to release previously enclosed drug.

In the following, lipid (s) are to be understood to mean all constituents of the liposome bilayer with the exception of the liposomally enclosed pharmaceutical substance The liposomes from the liposome components proposed according to the invention can be produced by various methods. The following examples explain the processes for the production of liposomes with lipophilic drugs for the lipid compositions according to the invention and are known per se from the prior art. [MJ Ostro, Liposomes, Marcel Dekker, New York, 1983; G. Gregroiadis, Liposome Technology Vol. I, Preparation of Liposomes, CRC Press Inc. Boca Raton, 1984]:

Mechanical methods

The hydration of the lipid-drug mixtures obtained from organic media or the hydration of lipids and drug without prior "film formation" from organic solution is carried out with aqueous dispersants.

The size of the liposomes resulting from spontaneous vesicle formation during hydration can be varied. This dispersion can take place through mechanical energy input of different origins, for example by simple hand shaking, use of shaking devices, by extrusion through membrane filters with a precisely defined pore size, extrusion under high pressure through various narrow nozzles, through the use of various stirring and mixing devices and through ultrasonication .

Solvent removal

Removal of an organic solvent from W / O emulsions, consisting of organic solvent, water, lipids and drug.

Injection method

Injection of organic lipid drug solutions into aqueous dispersants with or without subsequent removal of the organic solvent.

Detergent method

Detergent removal from lipid-drug-detergent micelles, for example via dialysis. Freeze drying method

Due to the spontaneous vesicle formation of freeze-dried lipid-drug mixtures, liposomes containing active substances are formed during the hydration. During the hydration of freeze-dried liposomes, drug-containing liposomes are reconstituted

Fπer-Tau method

Repeated freezing and thawing of aqueous lipid-drug systems results in liposome dispersions

Individual forms of administration of the liposome formulations according to the invention are listed below, but without restricting the variety of possible uses of the system according to the invention. Liposomes produced with the liposome components according to the invention can po, ι v, sc, ι c, dermal, intrapulmonal, nasal, ip, rectally, in ocular or be applied intracerebrally

The invention described will now be explained in the following examples. Various, other configurations will become apparent to the person skilled in the art from the present description. However, it is expressly pointed out that the examples and the description are only provided for illustration and are not to be regarded as a limitation of the invention

Examples

Preliminary note

General manufacturing method for the following examples

The lipids under consideration were weighed into a round-bottomed flask with a long neck and dissolved with a suitable mixture of chloroform and methanol, possibly using warmth. Drug dissolved in methanol was pipetted in. The solvent mixture was spun off on a rotary evaporator and dried. To completely remove residual solvent, the lipid film was subsequently dried in a vacuum drying cabinet. After gassing with nitrogen, the lipid film was stored at -18 ° C. until hydration. To prepare the liposomes, lipid film was hydrated with 5% (m / V) glucose solution. The hydration was carried out at 75 ° C. for about 4 hours, about 10-13 glass balls with a diameter of 6 mm being added to the batch to facilitate dispersion and hydration of the lipid-drug mixture. From time to time, the round bottom flask was manually during the hydration shaken vigorously. The resulting liposomes were subjected to ultrasonication to reduce the size. For this purpose, the liposome dispersion was transferred to thick-walled sonication glass and sonicated with the Branson Sonifier B 15 Cell Disruptor. The following device parameters were selected for the standard batch size of 10 ml. Schalistab 1/2 "; sonication time 20 minutes, sonication pulsed; duty cycle 70%; output control 8, temperature bath 50 ° C To remove metal debris, larger liposomes and non-hposomally enclosed medicinal product, the cooled preparation was first 15 min at 1900 g centrifuged, and then the centrifugation supernatant was pressed through a membrane filter with a pore size of 0.2 μm. The liposome size was determined in the filtrate and the preparation was stored for 24 hours at 4 ° C. and 24 hours at room temperature. The liposome size was always less than 100 nm on average Filtration through a membrane filter with a pore size of 0.2 μm, the liposome size, the drug content and the lipid content were determined in the filtrate. For investigations over the storage period, the batches were divided into two and after "filtration through bacteria-retaining filters" (DAB 10) at temperatures of 4 ° C. and Room temperature stored under the exclusion of light Table 1

Abbreviations of the lipids used

Abbreviation lipid

DSPG-Na distearoylphosphatidylglycerol, Na salt

HSPC hydrogenated soy phosphatidylcholine (trade name

Phospholipon® 100 H, Nattermann, Cologne (D))

CH cholesterol

Pl-Na phosphatidyl inositol, Na salt

DPPS Dipalmitolylphosphatidylsenn

DPPA dipalmitoylphosphatidyl acid

example 1

Influence of different lipids on the liposomal inclusion of BIIC 1996 BS

The four lipids DSPG-Na, Pl-Na, DPPS and DPPA were tested in combination with 30 mol% HSPC for their inclusion capacity with regard to BIIC 1996 BS. A lipid concentration of 5 μmol / ml and a drug concentration of 10.2 mg were used / ml Fig. 2 shows the corresponding result, according to which only the lipids containing glycerol and inositol showed a satisfactory result. The quotient D / L denotes the molar ratio of liposomally enclosed BIIC 1996 BS and lipid Example 2

Influence of phosphatidyl-glycerol on the liposomal inclusion of BIIC 1996 BS

HSPC / DSPG-Na was tested as a lipid mixture in varying compositions.

Tab. 2 summarizes the lipid mixtures examined:

Table 2

Examined lipid mixtures

HSPC DSPG-Na CH

[mol%] [mol%] [mol%]

70 30 0

50 50 0

30 70 0

0 100 0

49 21 30

35 35 30

21 49 30

0 70 30

0 85 15

0 55 45

0 40 60

27.75 64.75 7.5

25.5 59.5 15

16.5 38.5 45

12 28 60

The more DSPG-Na is added to the different lipid mixtures, the more active ingredient (BIIC 1996 BS) could be included liposomally. At the considered lipid concentration of 45 μmol / ml, the applied Production method without the addition of DSPG-Na no preparations can be produced with liposomes <200 nm

Figures 3-6 graphically represent the results

Example 3

Influence of the lipid concentration on the liposomal inclusion of BIIC 1996 BS For the lipid compositions HSPC / DSPG-Na / CH (21/49/30) and HSPC / DSPG-Na (30/70) the lipid concentrations were from 0 μmol / ml to 75 μmol / ml varies Fig. 7 shows that the amount of included BIIC 1996 BS increases with increasing lipid concentration, so that the drug content can be controlled

Example 4

Influence of the use concentration of the drug on the liposomal inclusion of BIIC 1996 BS

For the lipid compositions HSPC / DSPG-Na (30/70) and HSPC / DSPG-Na / CH (21/49/30), the drug concentrations were varied between 0 mg / ml to 10.2 mg / ml

FIG. 8 and FIG. 9 represent the results graphically, they demonstrate that with increasing amount of the drug used, the amount of the liposomally included drug increased linearly up to the saturation limit. The amount of BIIC 1996 BS included could thus be controlled excellently

Example 5

Influence of storage conditions and use concentration on the drug content of BIIC 1996 BS liposomes

For the lipid compositions HSPC / DSPG-Na (30/70) and HSPC / DSPG-Na / Cl (21/49/30), the drug concentrations were varied between 0 mg / ml to 10.2 mg / ml and the inclusion rates after 2 days Manufacturing and 28 days examined after manufacture. The storage conditions were 4 ° C and room temperature (19 - 24 ° C) with the exclusion of light. Figures 10 and 11 graph the results, showing that drug inclusion did not change significantly during the study period.

Example 6

Influence of storage conditions and use concentration on the size of BIIC 1996 BS liposomes

For the lipid compositions HSPC / DSPG-Na (30/70) and HSPC / DSPG-Na / CH (21/49/30), the drug concentrations were varied between 0 mg / ml to 10.2 mg / ml and the liposome size after production, Examined 2 days after manufacture and 28 days after manufacture. The storage conditions were 4 ° C and room temperature (19 - 24 ° C) with the exclusion of light.

Increasing BIIC 1996 BS levels stabilized the liposome size (Fig. 12). A cholesterol addition of 30 mol% of stabilized liposomes with maximally included drug with regard to size growth (FIG. 13).

Example 7

Stability of BIIC 1996 BS liposomes

Liposome dispersions of the lipid composition HSPC / DSPG-Na. (30/70) with the drug concentration 3.5 mg / ml and HSPC / DSPG-Na / CH (21/49/30) with the drug concentration 3.0 mg / ml were used in one Lipid concentration of 45 μmol / ml nebulized with the Respirgard II δ10 nebulizing system. The nozzle gas flow was 6 l / min, the nebulization time 22.53 min + 2.13 min (x + SD). Before and after nebulization, the nebulizing solution in the reservoir was examined for the drug content. Using the Andersen 1-AFCM Non-Viable Ambient Particie Sizing Sampler Mark II, spraying with water vapor saturated supply air, collected aerosol was also examined. Fig. 14 illustrates the great content stability of the liposomes under consideration under very strong mechanical stress, such as occurs during nozzle atomization. Explanation of the drawings

1 shows the structural structure of phosphatidylglycerols and phosphatidylinositols - in particular the structural formula of the sodium salt of phosphatidylglycerols and phosphatidylinositols [G Cevc, D Marsh, Phosphohpid Bilayers, Physical Pnnciples and Models, John Wiley & Sons Ine, New York, 1987, D Arnd , I Fichtner, Liposomes, Representation - Properties - Application, Akademie Verlag Berlin, 1986]

FIG. 2 Influence of different lipids on the liposomal inclusion of BIIC 1996 BS (example 1)

Inclusion rates 2 days after preparation Lipid composition HSPC / Lipid (30/70) use concentrations BIIC 1996 BS> 10 mg / ml

Lipid 5 μmol / ml The data shown are the arithmetic mean from 3 determinations. The error bars represent the standard deviation

3 shows the influence of phosphatidyl-glycerol on the liposomal inclusion of BIIC 1996 BS (example 2)

Inclusion rates 2 days after production. Use concentrations BIIC 1996 BS> 10 mg / ml

Lipid 45 µmol / ml

The data shown are the arithmetic mean values from 3 determinations. The error bars represent the standard deviation

4 shows the influence of phosphatidyl-glycerol on the liposomal inclusion of BIIC 1996 BS in three-component lipid systems with constant cholesterol content (example 2) Inclusion rates 2 days after production. Use concentrations: BIIC 1996 BS> 10 mg / ml

Lipid 45 μmol / ml The data shown are the arithmetic mean of 3 determinations. The error bars represent the standard deviation.

Fig. 5: shows the influence of phosphatidyl-glycerol on the liposomal

Inclusion of BIIC 1996 BS in two-component lipid systems with cholesterol (example 2).

(•) D / L = D / DSPG-Na (D) D / L = D / (DSPG-Na + CH) Inclusion rates 2 days after production. Use concentrations: BIIC 1996 BS> 10 mg / ml

Lipid 45 µmol / ml

The data shown are the arithmetic mean values from 3 determinations. The error bars represent the standard deviation.

Fig. 6: shows the influence of phosphatidyl-glycerol on the liposomal

Inclusion of BIIC 1996 BS in three-component systems with variable cholesterol content (example 2).

(•) D / L = D / (HSPC + DSPG-Na) (D) D / L = D / (HSPC + DSPG-Na + CH) Inclusion rates 2 days after production. Use concentrations: BIIC 1996 BS> 10 mg / ml

Lipid 45 µmol / ml

The data shown are the arithmetic mean values from 3 determinations. The error bars represent the standard deviation. shows the influence of the lipid concentration on the liposomal inclusion of BIIC 1996 BS (example 3)

(•) HSPC / DSPG-Na (30/70) (O) HSPC / DSPG-Na / CH (21/49/30) Inclusion rates 2 days after production. Use concentrations BIIC 1996 BS> 10 mg / ml

The data shown are the arithmetic mean values from FIG. 3

Provisions

The error bars represent the standard deviation

shows the influence of the use concentration of the drug on the liposomal inclusion of BIIC 1996 BS (Example 4)

Inclusion rates 2 days after preparation of lipid composition HSPC / DSPG-Na (30/70) use concentrations lipid 45 μmol / ml

Inclusion rates 2 days after preparation of lipid composition HSPC / DSPG-Na / CH (21/49/30) use concentrations lipid 45 μmol / ml

The data shown are the arithmetic mean values from 3 determinations. The error bars represent the standard deviation 381 PC17EP97 / 03108

16

shows the influence of the use concentration of the drug on the liposomal inclusion of BIIC 1996 BS (Example 5)

Inclusion rates 2 days after production and 28 days after storage at 4 ° C. and room temperature with the exclusion of light. Lipid composition HSPC / DSPG-Na / CH (30/70) use concentrations lipid 45 μmol / ml

shows the influence of storage conditions and use concentration of the drug on the liposomal inclusion of BIIC 1996 BS (Example 5)

Inclusion rates 2 days after production and 28 days after storage at 4 ° C. and room temperature with the light closed

Lipid composition HSPC / DSPG-Na / CH (21/49/30)

Use concentrations lipid 45 μmol / ml

The data shown are the arithmetic mean values from FIG. 3

Regulations The error bars represent the

Standard deviation

shows the influence of storage conditions and use concentrations of the drug on the size of BIIC 1996 BS liposomes (Example 6)

Liposome sizes after production (•), after 2 days (D), after 28 days, after storage at 4 ° C (■) and after 28 days storage at room temperature (19 - 24 ° C) (O) with the light closed

Lipid composition HSPC / DSPG-Na (30/70) use concentrations lipid 45 μmol / ml The data shown are the arithmetic mean values from 3 determinations. The error bars represent the standard deviation.

Fig. 13: shows the influence of storage conditions and use concentrations of the drug on the size of BIIC 1996 BS liposomes (Example 6).

Liposome sizes after production (•), after 2 days (D), after 28 days after storage at 4 ° C (■) and after 28 days storage at room temperature (19 - 24 ° C) (O) with the light closed.

Lipid composition: HSPC / DSPG-Na (21/49/30)

Use concentrations: Lipid 45 μmol / ml

The data shown are the arithmetic mean values from FIG. 3

Provisions. The error bars represent the

Standard deviation.

Fig. 14: shows nebulization stability of BIIC 1996 BS liposome dispersions (Example 7).

The liposome dispersions were nebulized using the Respirgard II δ10 system.

Use concentrations:

BIIC 1996 BS HSPC / DSPG-Na (30/70) 3.5 mg / ml

HSPC / DSPG-Na / CH (21/49/30) 3.0 mg / ml lipid concentration 45 μmol / ml

Nozzle gas flow 6 l / min; Misting time 22.53 + 2.13 min (x + SD). The data shown are the arithmetic mean of 5 determinations. The error bars represent the standard deviation.

Claims

claims

1. Use of phosphatidylglycerols of the general formula I and phosphatidylinositols of the general formula II

in which R- | and R2 in both general formulas independently of one another denotes a branched or unbranched alkyl radical of a natural, semisynthetically or fully synthetically producible fatty acid - saturated or unsaturated character - with 1 to 30 carbon atoms, for the production of a pharmaceutical preparation in the form of liposomes for poorly soluble pharmaceutical active substances.

2. Use according to claim 1, characterized in that R 1 or R 2 independently of one another are the alkyl radical of a saturated unpressurized fatty acid from the group formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oenanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid , Myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachic acid, behenic acid, lignoceric acid, cerotic acid or melissic acid.

3. Use according to claim 1, characterized in that R- | or R2 can independently of one another denote the alkyl radical of a saturated and branched fatty acid from the group of isobutyric acid, isovaleric acid, tubercolostearic acid.

4. Use according to claim 1, characterized in that R- | or R2 independently of one another can denote the alkyl radical of an unsaturated and unbranched fatty acid from the group consisting of acrylic acid, crotonic acid, palmitoleic acid, oleic acid, erucic acid.

5. Use according to claim 1, characterized in that R 1 or R 2 can independently denote the alkyl radical of a di-unsaturated and unbranched fatty acid from the group of sorbic acid or linoleic acid.

6. Use according to claim 1, characterized in that R- | or R2 can independently of one another denote the alkyl radical of a triple unsaturated and unbranched fatty acid from the group linolenic acid or elaostearic acid.

7. Use according to claim 1, characterized in that R- | or R2 can independently mean arachidonic acid, clupanodonic acid or docosahexaenoic acid.

8. Use according to any one of claims 1 to 7, characterized in that the phosphatidyl glycerols and phosphatidyl inositols are used in the form of the free acids or their salts.

9. Use according to claim 8, characterized in that the phosphatidyl glycerols and phosphatidyl inositols are used in the form of their alkali salts.

10. Use according to claim 9, characterized in that the phosphatidyl glycerols and phosphatidyl inositols are used in the form of their sodium salts.

11. Use according to one of claims 1 to 10, characterized in that the phosphatidylglycerols of the general formula I are the sodium salts of dimyristoylphosphatidylglycerol (DMPG-Na), dipalmitoylphosphatidylglycerol (DPPG-Na) and distearoylphosphatidylglycerol (DSPG-Na) in concentrations of 0 up to 100 mol% based on the constituents of the liposomal lipid bilayer.

12. Use according to one of claims 1 to 11, characterized in that the sodium salts of dimyristoylphosphatidylinositol (DMPI-Na), dipalmitoylphosphatidylinositol (DPPI-Na) and disteraroylphosphatidylinositol (DSPI-Na) as phosphatidylinositols of the general formula I in concentrations of up to 100 mol% based on the constituents of the liposomal lipid bilayer.

13. Use according to one of claims 1 to 12, characterized in that poorly water-soluble pharmaceutical active ingredients are used as medicaments.

14. Use according to claim 13, characterized in that poorly soluble neurokinin (tachykinin) antagonists are used as pharmaceutical active ingredients.

15. Use according to claim 14, characterized in that as neurokinin antagonists (+) camphor-3-carbonyl- (2S, 4R) -4-hydroxyprolyl- (2S) -2- naphthylalanyl- (2-methoxyphenyl) piperazide or 1 -Methylindol-3-yl-carbonyl- [4 (R) -hydrxoy] -L-prolyl- [3- (2-naphthyl)] - L-alanine-N-benzyl-N-methylamide can be used.

16. Use according to one of claims 1 to 12, characterized in that corticoids are used as active pharmaceutical ingredients.

17. Use according to one of claims 1 to 12, characterized in that flunisolide hemihydrate or beclomethasone dipropionate are used as pharmaceutical active ingredients.