CA2253285A1 - Pharmaceutical preparation in the form of liposomes - Google Patents

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

CA 022~328~ 1998-10-29 .

FIL~.~ ~'' ' ~. ' r T~

S018-582J.200 Pharmaceutical Preparation in the form of Liposomes The present invention relates to a pharmaceutical preparation in the form of liposomes, suitable for the solubilisation of poorly-soluble medicaments, especially poorly-soluble neurokinine antagonists such as e.g. (+)-camphor-3-carbonyl-(2S,4R)-4-hydroxypyrolyl(2S)-2-naphthylalanyl-(2-methoxyphenyl)piperazide [BIIC 1996 BS]
or l-methylindol-3-yl-carbonyl-[4(R)-hydroxy]-L-prolyl-[3-(2-naphthyl)]-L-alanine-N-benzyl-N-methylamide [FK 888].

Liposomes are generally ball-shaped structures - with a diameter of 25 nm up to several ~m - comprising one or more concentric lipid double layers with an aqueous interior. This kind of lipid vesicle can be created by mechanical fine distribution of phospholipids (e.g.
lecithin) in aqueous media. They do not only serve as membrane models in biochemistry or molecular biology but can also be used as carriers for medicaments.

A great number of active ingredients, which can be incorporated in liposomes or can be absorbed by liposomes, are known from the prior art. These kind of liposomal systems are always preferred when the active ingredient is to be released over a longer period of time, undesired medicament effects are to be reduced, the active ingredient is to be stabilised or liposomes are to serve as target-selective medicament vehicles [P. Tyle and B.P.
Ram, Targeted Therapeutic Systems, Marcel Dekker Inc., New York, 1990; G. Gregoriadis, Liposome Technology Vol. III, Targeted Drug Delivery and Biological Interaction, CRC
Press Inc., Boca Raton, 1984]. The above mentioned objectives were hitherto most adequately achieved by enclosing water soluble medicaments in liposomes [M.J.

CA 022~328~ 1998-10-29 ., 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].

In recent times, the aspect of medicament solubilisation using liposomes has gained increasing significance.
Within the framework of preliminary research work, the regularity of the inclusion of the liposomal medicament has, however, remained hitherto relatively unresearched.
In general, the objective of the medicament solubilisation is to have the medicament present in a mainly aqueous formulation with a dispersed-molecular distribution. This formulation can then be administered using known application methods.

The following criteria should be met by medicament preparations solubilised by liposomes:

The medicament should be included in liposome bilayers in dispersed-molecular form with the proviso that the ratio of included medicament to utilised quantity of lipids is as high as possible. In the same way, the medicament liposomes should have an active ingredient and stability range which is adapted to the intended purpose.

For many application forms it is indispensable to be able to produce sterile liposome preparations, for example by sterilisation filtration with membrane filters with 0.2 ~m pore diameter. Small liposomes, i.e. of liposome diameter ~200 nm are ideal for attaining satisfactory liposome stability during mechanical agitation. This, for example, is required during atomisation of aqueous liposome preparations by means of pneumatic jet atomisers for inhalative application. In order to avoid embolic infusion incidents, it must be guaranteed that the size of CA 022~328~ 1998-10-29 __ the injected liposomes on the one hand does not exceed a critical value, and on the other hand the liposomes must not form any aggregates of this critical size after intravenous administration. Only physiologically-harmless adjuvant substances are to be used as solubilising agents for use with patients in general, and for intravenous application in particular. The liposome components which have been suggested by way of example are suitable as natural bodily components, since for example on the one hand they are not toxic and on the other they have a good compatibility, and can be decomposed by the body without leaving a residue.

The objective of the present invention is henceforth to provide a medicament formulation on the basis of liposomes for the solubilisation of poorly-soluble medicaments, especially for neurokinine (tachykinine) antagonists, as disclosed in the general formula, the preferred ranges and in the embodiment examples of WO 95/30687. A principal objective of the present invention is to provide a medicament formulation on the basis of liposomes for the solubilisation of the active ingredients (+)-camphor-3-carbonyl-(2S,4R)-4-hydroxyprolyl-(2S)-2-naphthylalanyl-(2-methoxy-phenyl)piperazide [BIIC 1996 BS] and 1-methylindol-3-yl-carbonyl-[4(R)-hydroxy]-L-prolyl-[3-(2-naphthyl)]-L-alanine-N-benzyl-N-methylamide [FK 888] (cf.
Ann. Drug. Data Rep. 15 (1993) 252). In addition, liposomal inclusion compounds with the suggested compounds according to the invention can also be produced with corticoids - such as e.g. flunisolide hemihydrate or beclomethasone dipropionate.

BIIC 1996 is a non-selective neurokinine antagonist which binds to the NK1, NK2 and NK3 receptor with affinities in the nanomolar range. Surprisingly, it was discovered that the liposome formulations, according to the invention, for CA 022~328~ 1998-10-29 the solubilisation of pharmaceutical active ingredients, which are produced with the liposome components described in the following text, have special advantages. The liposome preparations which contain active substances according to the invention, hence solve the objective as stated above and also represent considerable progress in the solubilisation of poorly water-soluble lipophile medicaments.

The liposome compositions, according to the invention, distinguish themselves e.g. in the way that liposome-forming amphiphilic adjuvant substances, in which the physico-chemical character of the hydrophilic molecular portion is determined by glycerol or inositol, are especially suitable for incorporating large quantities of poorly-soluble medicament especially the neurokinine antagonists BIIC 1996 BS and FK 888, as mentioned above -in liposomes.

According to the invention, the liposome-forming adjuvant substances correspond to general formulas I and II of diagram 1, in which R1 and R2 in both general formulas, independently from one another, have a branched or unbranched alkyl group of a naturally, semi or fully synthetically producable fatty acid - of saturated or unsaturated character - with 1-30 carbon atoms.

Examples for saturated unbranched fatty acids are: formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hexanoic 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, melissic acid.

CA 022~328~ 1998-10-29 The following are an example of saturated branched fatty acids: isobutyric acid, isovaleric acid, tubercolostearic acid.

The following are examples of mono-unsaturated unbranched fatty acids: acrylic acid, crotonic acid, palmitoleic acid, oleic acid, erucic acid.

The following are examples of di-saturated unbranched fatty acids: sorbic and linoleic acid.

Examples of tri-saturated unbranched fatty acids are linolenic acid and elaostearic acid.

Examples for tetra- and penta-unsaturated unbranched fatty acids are arachidonic acid and clupanodonic acid respectively.

Docosahexanoic acid is an example of a hexa-unsaturated unbranched fatty acid.

The use of phosphatidylglycerols and phosphatidylinositols in the form of the free acids or their salts - especially in the form of the alkali salts - is preferred; use of the sodium salts is especially preferred.

The use of the following phosphatidylglycerols is especially preferred:

sodium salts of dimyristoylphosphatidylglycerol (DMPG-Na), dipalmitoylphosphatidylglycerol (DPPG-Na) and distearoylphosphatidylglycerol (DSPG-Na).

Use of the following compounds as phosphatidylinositols are especially preferred:

CA 022~328~ 1998-10-29 sodium salts of dimyristolphosphatidylinositol (DMPI-Na), dipalmitoylphosphatidylinositol (DPPI-Na) and distearoylphosphatidylinositol (DSPI-Na).

For the purposes of clarification of the structural composition of phosphatidylglycerols and phosphatidylinositols, Fig. 1 shows especially the structural formula of the sodium salt of phosphatidylglycerols and phosphatidylinosltols.
The liposome components according to the invention are characterised in that they can be added to any other liposome components in proportions of greater than 0 mol.
~ up to 100 mol. ~.
The liposomes produced by means of the liposome component parts according to the invention - especially BIIC 1996-containing liposomes - have the following advantages:

1. The content of pharmaceutically-active components can be strongly increased by addition of the liposome components according to the invention. For this reason, a high active ingredient concentration can be obtained by dispensing with the cost-intensive concentration increase of the remaining liposome constituents.

2. By variation of the molar proportion of liposome components according to the invention, the maximum inclusion of the medicament can be controlled over a wide area.

3. The liposome components according to the invention are indispensable for the simple production of liposomes which contain active ingredient in a size range of <200 nm.

CA 022~328~ 1998-10-29 4. The concentration of the solubilised medicament can be controlled by variation of the total lipid content.

5. The medicament enclosed in the liposome - especially the neurokinine antagonist BIIC 1996 BS - stabilises the liposomes with regard to their increase in size.

6. Liposomes with sub-maximum quantities of enclosed medicament can be stabilised with regard to their size increase by the addition of cholesterol.

7. Medicament containing liposomes show no tendency to release enclosed medicaments either in the case of mechanical agitation or extended storage.

In the following text, the term "lipid" or "lipids" refers to all component parts of the liposome bilayers with the exception of the medicament enclosed in the liposome.
The liposomes, comprising the liposome components suggested according to the invention, can be produced according to various processes. The following examples explain the processes for the manufacture of liposomes with lipophilic medicaments for the lipid compositions according to the invention, and are known per se from the prior art. [M. J. 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 medicament mixture extracted from organic media, or hydration of lipids and medicament CA 022~328~ 1998-10-29 without prior "film formation" from an organic solution, is carried out using aqueous dispersion means.

The liposomes which result from spontaneous vesicle formation during hydration can be varied in their size.
This dispersion can take place by mechanical energy input of various types - for example, simple shaking by hand, the use of agitation apparatus, by extrusion through a membrane filter with exactly-defined pore size, extrusion under high pressure through a variety of narrow jets, by the use of a variety of agitation and mixing appliances and by subjecting to ultrasonic treatment.

Removal of Solvent Removal of an organic solvent from W/O emulsions, comprising organic solvents, water, lipids and medicament.

Injection Method Injection of organic lipid-medicament solutions in aqueous dispersion means, with or without subsequent removal of the organic solvent.

Detergent Method Detergent removal from lipid-medicament-detergent miscellae, for example via dialysis.

Freeze-Dry Method Liposomes containing the active ingredient result from spontaneous vesicle formation of freeze-dried lipid-medicament mixtures during hydration. Liposomes containing the medicament are reconstituted during the hydration of freeze-dried liposomes.

CA 022~328~ 1998-10-29 Freeze-Thaw Method Repeated freezing and thawing of aqueous lipid-medicament systems results in the formation of liposome dispersions.

Individual application forms of the liposome formulations according to the invention, are listed in the following text without limiting the variety of possibilities for using the system according to the invention. Liposomes produced with the liposome components, according to the invention, can be administered p.o., i.v., s.c., dermally, intrapulmonary, nasally, i.p., rectally, i.m., ocularly or intercerebrally.
The described invention will be explained again in the following Example. Different formations will be apparent to the skilled person from the present description.
However, it should be expressly noted that the Examples and the description are only provided for the purposes of explanation and are not to be seen as a restriction of the invention.

CA 022~328~ 1998-10-29 .~_ EXAMPLES

Foreword:

General production methods for the following Examples:

The lipids in question were weighed in a round flask with a long neck and were dissolved in a suitable mixture of chloroform and methanol, optionally using heat.
Medicament dissolved in methanol was added by pipette.
The solvent mixture was evaporated down in a rotary evaporator and dried. The lipid film was re-dried in a vacuum oven for complete removal of residual solvent.
After degassing with nitrogen, the lipid film was stored at -18~C until it was hydrated. In order to produce the liposomes, lipid film was hydrated with glucose solution 5~ (m/V). Hydration was carried out for approximately 4 hours at 75~C, wherein approximately 10-13 glass balls with a diameter of 6 mm were added to the mixture to promote easier dispersion and hydration of the lipid-medicament mixture. From time to time, the round flask was agitated strongly by hand during hydration. The resulting liposomes were subjected to ultrasound treatment to reduce their size. For this reason, the liposome dispersion was decanted into thick-walled acoustic irradiation glasses and was irradiated with the Branson Sonifier B15 Cell Disruptor. The following apparatus parameters were selected for the standard mixture size of 10 ml: sonic rod 1/2~'; irradiation time 20 minutes, type of irradiation pulsed; duty cycle 70~; output control 8;
temperature bath 50~C. In order to remove metal dust, larger liposomes and medicament which was not enclosed in the liposomes, the cooled preparation was firstly centrifuged for 15 minutes at 1900 g, and following this the supernatent was pressed through a membrane filter with a pore width of 0.2 ~m. The liposome size was determined CA 022~328~ 1998-10-29 in the filtrate and the preparation was stored for 24 hours at 4~C and 24 hours at room temperature. The average liposome size was always below 100 nm. After repeated filtration through a membrane filter with a pore width of 0.2 ~m, the liposome size, the medicament content and the lipid content were determined in filtrate. For tests over the storage time, the batches were divided into two and following "filtration through a bacteria-retaining filter" (DAB 10) were stored at temperatures 4~C and room temperature with the exclusion of light.

Table 1 Abbreviations of the utilised lipids Abbreviation Lipid DSPG-Na Distearoylphosphatidylglycerol, Na-salt HSPC Hydrated soya-phosphatidylcholine (Trade name: Phospholipon~ 100 H, Company Nattermann, Cologne (D)) CH Cholesterol PI-Na Phosphatidylinositol, Na-salt DPPS Dipalmitolylphosphatidylserine 25 DPPA Dipalmitolylphosphatidylic acid CA 022~328~ 1998-10-29 ,._~ ,_ Example 1 The influence of various lipids on the liposomal inclusion of BIIC 1996 BS

The four lipids DSPG-Na, PI-Na, DPPS and DPPA were tested in a combination with 30 mol. ~ HSPC for their inclusion capacity with regard to BIIC 1996 BS. A lipid concentration of 5 ~mol/ml and a medicament concentration of 10.2 mg/ml were used. Diagram 2 shows the corresponding result, wherein only the glycerol and inositol-containing lipids showed a satisfactory result.
The quotient D/L represents the molar ratio of BIIC 1996 BS contained in the liposomes and lipid.
Example 2 Influence of phosphatidylglycerol on the liposomal inclusion of BIIC 1996 BS
HSPC/DSPG-Na in varying compositions as a lipid mixture was tested.

Table 2 summarises the tested lipid mixtures:

CA 022~328~ l998-l0-29 Table 2 Tested lipid mixtures 5 HSPC DSPG-Na CH
[mol-~] [mol-~] [mol-~]

2027.75 64.75 7.5 25. 5 59.5 15 16.5 38.5 45 25 The more DSPG-Na added to the various lipid mixtures, the more active ingredient (BIIC 1996 BS) could be included in the liposomes. No preparations with liposomes of <200 nm could be produced with the considered lipid concentration of 45 ~mol/ml with the applied production methods without 30 DSPG-Na addition.

Figures 3 - 6 show the results in graphic form.

CA 022~328~ 1998-10-29 Example 3 Influence of lipid concentration on the liposomal inclusion of BIIC 1996 BS.

The lipid concentrations of 0 ~mol/ml to 75 ~mol/ml were varied for the lipid compositions HSPC/DSPG-Na/CH
(21/49/30) and HSPC/DSPG-Na (30/70). Diagram 7 shows that the quantity of BIC 1996 BS increases with increasing lipid concentration, and hence the medicament content can be controlled.

Example 4 Influence of the applied concentration of medicament on the liposomal inclusion of BIIC 1996 BS.

The medicament concentrations were varied between 0 mg/ml to 10.2 mg/ml for the lipid compositions HSPC/DSPG-Na (30/70) and HSPC/DSPG-Na/CH (21/49/30).

Figures 8 and 9 show the results in graphic form; they show that the quantity of liposomally-included medicament increases in a linear fashion until it reaches the saturation threshold with increasing quantities of applied medicament. In this way, the quantity of included BIIC
1996 BS can be controlled in an excellent manner.

Example 5 Influence of storage conditions and applied concentration on the medicament content of BIIC 1996 BS liposomes The medicament concentrations were varied between 0 mg/ml to 10.2 mg/ml, for the lipid compositions HSPC/DSPG-Na (30/70) and HSPC/DSPG-Na/Cl (21/49/30), and the inclusion CA 022~328~ l998-l0-29 ." . ._ rates were tested at 2 days after production and 28 days after production. The storage conditions were 4~C and room temperature (19-24~C), with light being excluded.
Figures 10 and 11 represent the results in graphic form, 5 these show that the medicament inclusion did not significantly alter during the period of the test.

Example 6 Influence of storage conditions and applied concentration on the size of BIIC 1996 BS liposomes The medicament concentrations were varied between O mg/ml and 10. 2 mg/ml for the lipid compositions HSPC/DSPG-Na (30 / 70) and HSPC/DSPG-Na/CH (21 / 49 / 30), and the liposome size was tested after production, 2 days after production and 28 days after production. The storage conditions were 4~C and room temperature (19-24~C), light being excluded.

20 Increasing quantities of BIIC 1996 BS stabilised the liposome size (Fig. 12) . An addition of 30 mol~
cholesterol stabilised liposomes with less than the maximum inclusion of medicament with regard to the increase in size (Fig. 13) .
Example 7 Stability of BIIC 1996 BS liposomes 30 Liposome dispersions of lipid composition HSPC/DSPG-Na (30/70) with the medicament concentration 3.5 mg/ml and HSPC/DSPG-Na/CH (21/49/30) with the medicament concentration 3.0 mg/ml were atomised with a lipid concentration of 45 ~mol/ml with the Respirgard II ~ 10-35 atomising system. The jet gas flow was 6 l/min,atomisation duration was 22.53 min + 2.13 min (x + SD).

CA 022~328~ 1998-10-29 __ Before and after the atomising, the atomiser solution in the reservoir was tested for medicament content. Captured aerosol was also tested by means of the Andersen 1-AFCM
Non-Viable Ambient Particle Sizing Sampler Mark II, driven by water steam-saturated air. Fig. 14 clarifies the high content stability of the examined liposomes in the case of very strong mechanical load, as occurs during jet atomising.

Explanation of the Diagrams Fig. 1: shows the structural composition of phosphatidylglycerols and phosphatidyl-inositols -especially the structural formula of the sodium salt of phosphatidyl- glycerols and phosphatidylinositols [G.
Cevc, D. Marsh, Phospholipid Bilayers, Physikal Principles and Models, John Wiley & Sons Inc., New York, 1987; D.
Arndt, I. Fichtner, Liposomen, Darstellung - Eigenschaften - Anwendung, Akademie Verlag Berlin 1986].
Fig. 2: influence on various lipids on the liposomal inclusion of BIIC 1996 BS (Example 1).

Inclusion rates 2 days after production.
Lipid composition: HSPC/Lipid (30/70) Applied concentration: BIIC 1996 BS >10 mg/ml Lipid: 5 ~mol/ml The data shown refers to the arithmetic mean value from 3 tests.
The error bar represents the standard deviation.

Fig. 3: shows the influence of phosphatidylglycerol on the liposomal inclusion of BIIC 1996 BS (Example 2).
Inclusion rates 2 days after production.

CA 022~328~ l998-l0-29 ,_~

Utilised concentrations: BIIC 1996 BS > 10 mg/ml Lipid 45 ~mol/ml The data shown refers to the arithmetic mean value from 3 tests.
The error bar represents the standard deviation.

Fig. 4: shows the influence of phosphatidylglycerol on the liposomal inclusion of BIIC 1996 BS in three component lipid systems with constant cholesterol proportions (Example 2).

Inclusion rates 2 days after manufacture.
Utilised concentrations: BIIC 1996 BS > 10 mg/ml Lipid 45 ~mol/ml The data shown refers to the arithmetic mean value from 3 tests.
The error bar represents the standard deviation.
Fig. 5: shows the influence of phosphatidylglycerol on the liposomal inclusion of BIIC 1996 BS in two component lipid systems with cholesterol (Example 2).

(-) D/L = D/DSPG-Na (~) D/L = D/(DSPG-Na + CH) Inclusion rates 2 days after production.
Utilised concentrations: BIIC 1996 BS > 10 mg/ml Lipid 45 ~mol/ml The data shown refers to the arithmetic mean value from 3 tests.
The error bar represents the standard deviation.

CA 022~328~ 1998-10-29 Fig. 6: shows the influence of phosphatidylglycerol on the liposomal inclusion of BIIC 1996 BS in three component systems with variable cholesterol proportions (Example 2).

(-) D/L = D/HSPC-Na (~) D/L = D/(HSPC-Na + DSPG-Na + CH) Inclusion rates 2 days after production.
Utilised concentrations: BIIC 1996 BS ~ 10 mg/ml Lipid 45 ~mol/ml The data shown refers to the arithmetic mean value from 3 tests.
The error bar represents the standard deviation.
Fig. 7: shows the influence of the lipid concentration on the liposomal inclusion of BIIC 1996 BS (Example 3).

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

The data shown refers to the arithmetic mean value from 3 tests.
The error bar represents the standard deviation.

Fig. 8: shows the influence of the utilised concentration of the medicament on the liposomal inclusion of BIIC 1996 BS (Example 4).

Inclusion rates 2 days after production.
Lipid composition: HSPC/DSPG-Na (30/70) Utilised concentration: Lipid 45 ~mol/ml CA 022~328~ l998-l0-29 The data shown refers to the arithmetic mean value from 3 tests.
The error bar represents the standard deviation.

5 Fig. 9: shows the influence of the utilised concentrations of the medicament on the liposomal inclusion of BIIC 1996 BS (Example 4) .

Inclusion rates 2 days after production.
Lipid composition: HSPC/DSPG-Na/CH (21/49/30) Utilised concentrations: Lipid 45 ~mol/ml The data shown refers to the arithmetic mean value from 3 tests.
15 The error bar represents the standard deviation.

Fig. 10: shows the influence of the utilised concentrations of the medicament 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, light being excluded.
Lipid composition: HSPC/DSPG-Na/CH (30/70) Utilised concentrations: Lipid 45 ~mol/ml The data shown refers to the arithmetic mean value from 3 tests.
The error bar represents the standard deviation.

30 Fig. 11: shows the influence of storage conditions and utilised concentration of the medicament on the liposomal inclusion of BIIC 1996 BS (Example 5) .

Inclusion rates 2 days after production and 28 days after 35 storage at 4~C and room temperature, light being excluded.
Lipid composition: HSPC/DSPG-Na/CH (21/49/30) CA 022~328~ 1998-10-29 _ _ Utilised concentrations: Lipid 45 ~mol/ml The data shown refers to the arithmetic mean value from 3 tests.
The error bar represents the standard deviation.

Fig. 12: shows the influence of storage conditions and utilised concentrations of the medicament on the size of BIIC 1996 BS liposomes (Example 6).
Liposome sizes after production (-), after 2 days (~), after 28 days, after storage at 4~C (-) and after 28 days storage at room temperature (19-24~C) (O), light being excluded.
Lipid composition: HSPC/DSPG-Na (30/70) Utilised concentrations: Lipid 45 ~mol/ml The data shown refers to the arithmetic mean value from 3 tests.
The error bar represents the standard deviation.

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

Liposome sizes after production (-), after 2 days (~), after 28 days, after storage at 4~C (-) and after 28 days storage at room temperature (19-24~C) (O), light being excluded.

Lipid composition: HSPC/DSPG-Na (21/49/30) Utilised concentrations: Lipid 45 ~mol/ml The data shown refers to the arithmetic mean value from 3 tests.

CA 022~328~ 1998-10-29 __ The error bar represents the standard deviation.

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

The liposome dispersions were atomised with the Respirgard II ~ 10-System.

Utilised concentrations:
BIIC 1996 BS HPSC/DSPG-Na (30/70) 3.5 mg/ml HSPC/DSPG-Na/CH (21/49/30) 3.0 mg/ml Lipid concentration: 45 ~mol/ml Jet gas flow 6 l/min; atomisation duration 22.53 + 2.13 min (x + SD).
The data shown refers to the arithmetic mean value from 5 tests.
The error bar represents the standard deviation.

Claims (17)

Claims

1. The use of phosphatidylglycerols of general Formula I
and phosphatidyl- inositols of general Formula II

wherein R1 and R2 in both general formulas, independently from one another, denote a branched or unbranched alkyl group of a naturally, semi- or fully-synthetically producible fatty acid - of 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 ingredients.

2. Use according to claim 1, characterised in that R1 or R2, independently from one another, can denote the alkyl group of a saturated unbranched fatty acid from the group formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hexanoic 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, characterised in that R1 or R2, independently from one another, can denote the alkyl group of a saturated and branched fatty acid from the group isobutyric acid, isovaleric acid, tubercolostearic acid.

4. Use according to claim 1, characterised in that R1 or R2, independently from one another, can denote the alkyl group of an unsaturated and unbranched fatty acid from the group acrylic acid, crotonic acid, palmitoleic acid, oleic acid and erucic acid.

5. Use according to claim 1, characterised in that R1 or R2, independently from one another, can denote the alkyl group of a di-unsaturated and unbranched fatty acid from the group sorbic acid or linoleic acid.

6. Use according to claim 1, characterised in that R1 or R2, independently from one another, can denote the alkyl group of a tri-unsaturated and unbranched fatty acid from the group linolenic acid or elaostearic acid.

7. Use according to claim 1, characterised in that R1 or R2, independently from one another, can denote arachidonic acid, clupanodonic acid or docosahexanoic acid.

8. Use according to one of claims 1 to 7, characterised in that the phosphatidyl-glycerols and phosphatidylinositols are used in the form of the free acids or the salts thereof.

9. Use according to claim 8, characterised in that the phosphatidylglycerols and phosphatidylinositols are used in the form of their alkali salts.

10. Use according to claim 9, characterised in that the phosphatidylglycerols and phosphatidylinositols are used in the form of their sodium salts.

11. Use according to one of claims 1 to 10, characterised in that as phosphatidylglycerols of general Formula I, the sodium salts of dimyristoylphosphatidylglycerol (DMPG-Na), dipalmitoylphosphatidylglycerol (DPPG-Na) and distearoylphosphatidylglycerol (DSPG-Na) are used in concentrations from 0-100 mol. %, based on the component parts of the liposomal lipid double layer.

12. Use according to one of claims 1 to 11, characterised in that as phosphatidylinositols of general Formula I, the sodium salts of dimyristoylphosphatidylinositol (DMPI-Na), dipalmitoylphosphatidylinositol (DPPI-Na) and distearoylphosphatidylinositol (DSPI-Na) are used in concentrations from 0-100 mol. % based on the component parts of the liposomal lipid double layer.

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

14. Use according to claim 13, characterised in that poorly-soluble neurokinine (tachykinine) antagonists are used as pharmaceutical active ingredients.

15. Use according to claim 14, characterised in that (+)- camphor-3-carbonyl-(2S,4R)-4-hydroxyprolyl-(2S)-2-naphthylalanyl-(2-methoxyphenyl)piperazide or 1-methylindol-3-yl-carbonyl-[4(R)-hydroxy]-L-prolyl-[3-(2-naphthyl)]-L-alanine-N-benzyl-N-methylamide are used as neurokinine antagonists.

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

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