Aggregates with increased deformability, comprising at least three amphipats, for improved transport through semi-permeable barriers and for the non-invasive drug application in vivo, especially through the skin

• US 20040105881A1
• Filed: 02/04/2003
• Published: 06/03/2004
• Est. Priority Date: 10/11/2002
• Status: Abandoned Application

• Current Assignee: IDEA AG
• Original Assignee: IDEA AG
• Inventors: Cevc, Gregor, Vierl, Ulrich
• Application Number:
  US10/357,618
• Publication Number:
  US 20040105881A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/16 containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The invention describes combinations of at least three amphipatic substances forming aggregate suspensions in a polar liquid. Judicious choice of system components, which differ at least 2-times to 10-times in solubility, ensures said aggregates to have extended, unusually adaptable surfaces. This is probably due to simultaneous action on said aggregates of at least two more soluble substances amongst said three system components, at least one of which is an active ingredient and preferably a drug; the third component, alternatively, can take the role of a drug. The patent further deals with the use of said combinations in pharmaceutical preparations capable of transporting drugs into the body of warm blood creatures. This is made possible by the drug loading capability of said aggregates with the highly flexible and deformable coating, which renders the resulting drug carriers highly adaptable. The patent finally reveals suitable methods and favourable conditions for carrier manufacturing and application.

Claims

1. Preparation based on a combination of at least one first (membrane forming component MFC), at least one second (membrane destabilising component MDC), and at least one third (membrane destabilising component MDC) amphipatic component suspended in a suitable liquid medium in the form of corresponding mixed amphipat aggregates with extended surface (ESAs) with one or a few mixed amphipat coating(s), which are preferably bilayer like, wherein said ESAs formed by a combination of

all three said components have surfaces in contact with said liquid medium that are at least 50% more extended, on the average, than the typical surfaces of aggregates comprising the said at least one second and at least one third amphipatic component alone, at the same concentrations and, in case, after adjustment for the physico-chemical effects of resulting from the absence of said first amphipatic compound (MFC)

for application, administration or transport of an active ingredient, which can be one of the three amphipatic components, especially for biological, medical, immunological, or cosmetic purposes, into and through the pores in semi-permeable barriers or other constrictions, such as through the skin of warm blood creatures or the like.

5. A combination according to claims 1 to 4,

wherein the said extended surfaces are in the form of membrane surfaces.

6. A combination according to any of preceding claims,

wherein the said at least one second substance increases the flexibility of extended surfaces comprising said at least one first, at least one second, and at least one third substance in comparison with the surfaces formed merely by an at least one first substance or else with the surfaces formed by at least one first and at least one third substance.

7. A combination according any of preceding claims,

wherein the said at least one second and one third substance together increase the permeability of extended surfaces containing the said at least one first, at least one second, and at least one third substance, in comparison with the surfaces formed merely by the at least one first substance or else with the surfaces formed by at least one first and at least one third substance.

8. A combination according to any of preceding claims,

wherein the said at least one second substance or the said at least one third substance increases the ability to tolerate high curvature, as assessed by relative stability of said extended surface comprising said one first, said one second and said one third substance against enforced higher curvature during passing through a constriction with maximum diameter at least 1.4 times smaller than the average diameter of an extended surface formed by an at least one first substance alone.

9. A combination according to any of preceding claims,

wherein the at least one first substance and the at least one second substance or the at least one third substance differ in solubility on the average at least 10-fold.

10. A combination according to any of preceding claims,

wherein the at least one second substance and the at least one third substance differ in solubility on the average at least 2-fold.

11. A combination according to any of preceding claims,

wherein the at least one second substance or the at least one third substance have the hydrophilicity-lipophilicity ratio between 10 and 20.

12. A combination according to any of preceding claims,

wherein the concentration of said at least one second substance used in the combination with said one first and said one third substance is below 80% of the concentration that would be needed to render the aggregates comprising only said one first and said one second substance as adaptable to ambient stress as the selected combination of all at least three substances, whereby the said one second and said one third substance can exchange roles.

13. A combination according to any of preceding claims,

wherein the concentration of said at least one second substance or of said at least one third substance, as the case may be, amounts to at least 0.1% of the relative concentration as defined in claim 8.

14. A combination according to any of preceding claims,

wherein the concentration of said at least one second or of said at least one third substance amounts to 1-80% of the relative concentration as defined in claim 8.

15. The combination according to any of preceding claim,

wherein relative concentration of said at least one third substance used in combination with said one first and said one second substance is above 0.1% of maximum possible concentration of the said at least one third substance in the system,

a) as defined in terms of the solubility of said third substance in the system or in said at least three-component aggregates, or else

b) as determined by the negative action of said at least one third substance on the stability of said at least three-component aggregates,

whereby the said one third and one second substance can also exchange roles.

16. The combination according to any of preceding claims,

wherein relative concentration of said at least one third substance used in combination with said one first and with said one second substance is between 1% and 99% of maximum possible concentration of said at least one third substance,

a) as defined in terms of the solubility of said third substance in the system or in said at least three-component aggregates,

b) or else as determined by the detrimental effect of said at least one third substance on the stability of said at least three-component aggregates,

whereby the said one third and one second substance can also exchange roles.

17. The combination according to any of preceding claims,

wherein relative concentration of said at least one third substance used in combination with the said one first and the said one second substance is between 10% and 95% of the maximum possible concentration of said at least one third substance, as defined in terms of the third substance solubility in the system or in said aggregates, or else as determined by the detrimental effect of said at least one third substance on the stability of said at least three-component aggregates, whereby the said one third and one second substance can also exchange roles.

18. The combination according to any of preceding claims,

wherein relative concentration of said at least one third substance used in combination with the said one first and the said one second substance is between 25% and 90% of the maximum possible concentration of said at least one third substance, as defined in terms of the third substance solubility in the system or in said aggregates, or else as determined by the detrimental effect of said at least one third substance on the stability of said at least three-component aggregates, whereby the said one third and one second substance can also exchange roles.

19. The combination according to any of preceding claims,

wherein the total dry mass of all at least three amphipatic substances, which together form highly adaptable aggregates with an extended surface, is between 0.01 weight-% and 50 weight-%.

20. The combination according to any of preceding claims,

wherein total dry mass of all at least three substances, which together form highly adaptable aggregates with an extended surface, is between 0.5 weight-% and 30 weight-%.

21. The combination according to any of preceding claims,

wherein total dry mass of all at least three substances, which together form highly adaptable aggregates with an extended surface, is between 1 weight-% and 15 weight-%.

22. A combination according to any of preceding claims,

wherein the extended surfaces with a high adaptability, which contain said at least three substances, have an average curvature corresponding to an average radius between 15 nm and 5000 nm.

23. A combination according to any of preceding claims,

wherein the extended surfaces with a high adaptability, which contain said at least three substances, have an average curvature corresponding to an average radius between 30 nm and 1000 nm.

24. A combination according to any of preceding claims,

wherein the extended surfaces with a high adaptability, which contain said at least three substances, have an average curvature corresponding to an average radius between 40 nm and 300 nm.

25. A combination according to any of preceding claims,

wherein the extended surfaces with a high adaptability, which contain said at least three substances, have an average curvature corresponding to an average radius between 50 nm and 150 nm.

26. The combination of substances according to any of preceding claims,

wherein the concentration and the composition of the electrolyte in which the extended surfaces with at least one first, at least one second, and at least one third substance are suspended, and which comprises mono and/or oligovalent ions, is chosen to have ionic strength between I=0.001 and I=1.

27. The combination of substances according to any of preceding claims,

wherein the concentration and the composition of the electrolyte, in which the extended surfaces with at least one first, at least one second, and at least one third substance are suspended, and which comprise mono and/or oligovalent ions, is chosen to have pH value

a) in the vicinity of the logarithm of the apparent ionisation constant (pKa) of said at least one second substance, if the latter is mono-ionizable, or in the vicinity of such pKa value that maximises the solubility of said at least one second substance, if the latter has several ionizable groups, or else

b) in the vicinity of pH optimum for the most rapidly decaying or the otherwise most sensitive amongst the said at least three substances, if the said at least one second substance is not ionizable.

28. The combination of substances according to any of preceding claims,

wherein the pH value of the polar medium in which the ESAs comprising at least one first, at least one second, and at least one third substance are suspended is between pH=pKa−

3 and pH=pKa+3.

29. The combination according to any of preceding claims,

wherein the at least one first substance being less soluble in the liquid medium, and/or being the surface-building substance in the system, is a lipid, whereas the at least one second substance being more soluble in the liquid medium and/or increasing the tolerable surface curvature or adaptability of said extended surface, is a membrane destabilising amphipat, which is typically a surfactant, and said at least one third substance is either a biologically active amphipatic ingredient, which has a capability of its own to increase the tolerable surface curvature, or adaptability of said extended surface, or else is a different surfactant different from the said at least second substance.

30. The combination according to any of preceding claims,

wherein the molecules are arranged in the form of minute fluid droplets suspended or dispersed in a liquid medium and surrounded by a coating of one or several layers of the at least one first substance, which is capable of self-aggregation, and of at least one second substance and of at least one third substance, which are both amphipatic, such that

a) the former substance and the latter two substances differ in solubility in a suitable liquid medium at least 10-fold, or such that

b) the average radius of homo-aggregates of the more soluble amongst the at least one second and third substance or of hetero-aggregates of the at least one first, the at least one second and the at least one third substance is smaller than the average radius of homo-aggregates of said at least one first substance, which is the least soluble amongst the three.

31. Combination according to any of preceding claims,

wherein the at least one first substance is a polar or a non-polar, surface-forming lipid.

32. Combination according to any of preceding claims, wherein the at least one first substance in extended surfaces is capable of forming bilayer membranes and preferably forms bilayers on its own.

33. Combination according to any of preceding claims,

wherein the solubility of the at least one first substance in a polar liquid medium is between 10⁻

12 M and 10<sup>−

7</sup>M.

34. Combination according to any of preceding claims,

wherein the at least one first substance forming extended surfaces is selected from the group comprising lipids, lipoids from a biological source, corresponding synthetic lipids, or modifications thereof.

35. Combination according to any of preceding claims,

wherein said at least one first substance forming extended surfaces is selected from the group comprising glycerides, glycolipids, glycerophospholipids, isoprenoidlipids, sphingolipids, steroids, sterines or sterols, sulphur-containing lipids, lipids containing at least one carbohydrate residue, or other polar fatty derivatives.

36. Combination according to any of preceding claims,

wherein said at least one first substance forming extended surfaces is selected from the group comprising phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids, phosphatidylserines, sphingomyelins, sphingophospholipids, glycosphingolipids, cerebrosides, ceramidpolyhexosides, sulphatides, sphingoplasmalogenes, or gangliosides.

37. Combination according to any of preceding claims,

wherein said extended surface-forming substance is selected from the group comprising lipids with one or two, not necessarily identical, fatty chains, especially with acyl-, alkanoyl-, alkyl-, alkylene-, alkenoyl-, alkoxy, or chains with omega-cyclohexyl-, cyclo-propane-, iso- or anteiso-branched segments, or the corresponding chains mixtures.

38. Combination according to any of preceding claims,

wherein said substance that forms extended surfaces is selected from the group comprising lipids with n-decyl, n-dodecyl (lauryl), n-tetradecyl (myristyl), n-hexadecyl (cetyl), n-octadecyl (stearyl), n-eicosyl (arachinyl), n-docosyl (behenyl) or n-tetracosyl (lignoceryl), 9-cis-dodecenyl (lauroleyl), 9-cis-tetradecenyl (myristoleyl), 9-cis-hexadecenyl (palmitoleinyl), 9-cis-octadecenyl (petroselinyl), 6-trans-octadecenyl (petroselaidinylj, 9-cis-octadecenyl (oleyl), 9-trans-octadecenyl (elaidinyl), 9-cis-eicosenyl (gadoleinyl), 9-cis-docosenyl (cetoleinyl) or n-9-cis-tetracosoyl (nervonyl), n-decyloxy, n-dodecyloxy (lauryloxy), n-tetradecyloxy (myristyloxy), n-hexadecyloxy (cetyloxy), n-octadecyloxy (stearyloxy), n-eicosyloxy (arachinyloxy), n-docosoyloxy (behenyloxy) or n-tetracosoyloxy (lignoceryloxy), 9-cis-dodecenyloxy (lauroleyloxy), 9-cis-tetradecenyloxy (myristoleyloxy), 9-cis-hexadecenyloxy (palmitoleinyloxy), 6-cis-octadecenyloxy, (petroselinyloxy), 6-trans-octadecenyloxy (petroselaidinyloxy), 9-cis-octadecenyloxy (oleyloxy), 9-trans-octadecenyloxy (elaidinyloxy), and 9-cis-eicosenyl (gadoleinyloxy), 9-cis-docosenyl (cetoleinyloxy) or n-9-cis-tetracosoyl (nervonyloxy), n-decanoyloxy, n-dodecanoyloxy (lauroyloxy), n-tetradecanoyloxy (myristoyloxy), n-hexadecanoyloxy (palmitoyloxy) I n-octadecanoyloxy (stearoyloxy), n-eicosanoyloxy (arachinoyloxy), n-n-docosoanyloxy (behenoyloxy) and n-tetracosanoyloxy (lignoceroyloxy), 9-cis-dodecenyloxy (lauroleoyloxy), 9-cis-tetradecenoyloxy (myristoleoyloxy), 9-cis-hexadecenoyloxy (palmitoleinoyloxy), 6-cis-octadecenoyloxy (petroselinoyloxy), 6-trans-octadecenoyloxy (petroselaidinoyloxy), 9-cis-octadecenoyloxy (oleoyloxy), 9-trans-octadecenoyloxyelaidinoyloxy), and 9-cis-eicosenoyloxy (gadoleinoyloxy), 9-cis-docosenoyloxy (cetoleinoyloxy) and 9-cis-tetracosenoyloxy (nervonoyloxy) or the corresponding sphingosine derivative chains.

39. Combination according to any of preceding claims,

wherein said at least one second substance is a surfactant.

40. Combination according to any of preceding claims,

wherein said surfactant is selected from the group comprising nonionic, zwitterionic, anionic and cationic surfactants.

41. Combination according to any of preceding claims,

wherein said surfactant has the solubility in a polar liquid in which the extended surfaces are prepared between 10⁻

6 M and 10<sup>−

2</sup> M.

42. Combination according to any of preceding claims,

wherein said surfactant is selected from the group comprising long-chain fatty acids or long chain fatty alcohols, long chain fatty ammonium salts, such as alkyl- or alkenoyl-trimethyl-, -dimethyl- and -methyl-ammonium salts, alkyl- or alkenoyl-sulphate salts, or monovalent salts of cholate, deoxycholate, glycocholate, glycodeoxycholate, taurodeoxycholate, taurocholate, acyl- or alkenoyl-dimethyl-aminoxides, long fatty chain, for example alkanoyl, dimethyl-aminoxides and especially dodecyl dimethyl-aminoxide, long fatty chain, for example alkyl-N—

, methylglucamides and alkanoyl-N-methylglucamides, long fatty chain-N,N-dimethylglycines, for example N-alkyl-N,N-dimethylglycines, 3-(long fatty chain-dimethylammonio)-alkanesulphonates, for example 3-(acyldimethylammonio)-alkanesulphonates, long fatty chain derivatives of sulphosuccinate salts, long fatty chain-sulphobetaines, for example N-acyl-sulphobetaines, long fatty chain betaines, polyethylen-glycol-acylphenyl ethers, polyethylene-long fatty chain-ethers such as polyethylene-acyl ethers, polyethyleneglycol-iso long fatty chain ethers, such as polyethyleneglycol-isoacyl ethers, polyethyleneglycol-sorbitane-long fatty chain esters, for example polyethyleneglycol-sorbitane-acyl esters and especially polyethylenglykol-monolaurate (e.g. Tween

     20), polyethylenglykol-sorbitan-monooleate (e.g. Tween

     80), polyhydroxyethylene-long fatty chain ethers, for example polyhydroxyethylene-acyl ethers (Brij series), or the corresponding polyhydroxyethylene-acyl esters (Myrj series) and polyethoxylated castor oil 40 (Cremophor EL), sorbitane-mono long fatty chain, for example alkylate (Arlacel or Span series), long fatty chain —

N-methylglucamides, such as acyl-N-methylglucamides or alkanoyl-N-methylglucamides, long fatty chain sulphates, for example alkyl-sulphates and their salts;

long fatty chain thioglucosides, such as alkylthioglucosides, long fatty chain derivatives of various carbohydrates, such as pentoses, hexoses and disaccharides, especially alkyl-glucosides and maltosides;

further lysolipids, such as long fatty chains derivatives of common phospholipids, especially lyso-glycerophosphatidylcholine (lysolecithin), lyso-glycerophosphatidylethanolamine (lysokephalin), lyso-glycerophosphatidic acid, lyso-glycerophosphorylglycerol, lyso-glycerophosphorylserine, corresponding short-chain phospholipids, and membrane destabilising oligo or polypeptides.

43. Combination according to any of preceding claims,

wherein the at least one second substance is charged if the at least one third substance is uncharged, and the at least one second substance is uncharged if the at least one third substance is charged, similar preferred combinations also being possible for the said at least one first and one second or for the said at least one first and one third substance.

44. Combination according to any of preceding claims,

wherein the surface, formed by the at least one first, one second and one third substance, at least one of which is charged, contains between 1% and 75% of the charged component.

45. Combination according to any of preceding claims,

wherein the surface, formed by the at least one first, one second and one third substance, at least one of which is charged, contains between 5% and 50% of the charged component.

46. Combination according to any of preceding claims,

wherein the surface, formed by the at least one first, one second and one third substance, at least one of which is charged, contains between 10% and 30% of the charged component.

47. Combination according to any of previous claims,

wherein the surface-supporting at least one first substance is a phosphatidylcholine, a phosphatidylethanolamine-N-mono- or N-di-methyl, phosphatidic acid or its methyl ester, phosphatidylserine and/or phosphatidylglycerol and the at least one second substance which on its own forms small aggregates is a lysophospholipid, especially a lysophosphatidic acid, lysomethylphosphatidic acid, lysophosphatidylglycerol, lysophosphatidylcholine, a partially N-methylated lysophosphatidylethanolamine, a monovalent salt of cholate, deoxycholate, glycocholate, glycodeoxycholate, taurocholate, or a sufficiently polar sterol derivative, a laurate, myristate, palmitate, oleate, palmitoleate, elaidate or other long-chain fatty acid salt and/or a Tween-, a Myrj-, or a Brij-surfactant, or a Triton, a long-chain fatty sulphonate, -sulphobetaine, —

N-glucamide or -sorbitane (Arlacel or Span) surfactant.

48. Combination according to any of preceding claims,

wherein the at least one third substance, if not a surfactant different from the at least one second substance, but otherwise selected from similar surfactant classes, is a biologically active amphipat whibh can destabilise lipid membranes.

49. Combination according to any of preceding claims,

wherein the solubility of at least one third or of one second substance in a polar liquid is between 5×

1 0-6 M and 1 M.

50. Combination according to any of preceding claims,

wherein the at least one third amphipat or the at least one second amphipat adsorbs to the surface of lipid bilayer membrane but is well miscible with or soluble in the polar liquid in which the said extended surfaces are formed.

51. Combination according to any of previous claims,

wherein the at least one third or one second substance is a drug.

52. Combination according to any of preceding claims,

wherein the amphipatic compound with biological activity, which can act as a drug, is a substituted ammonium compound of the formula

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 cycle-C3-C6-alkyl-C1-C3-alkyl, or two of the radicals Rb, Rc and Rd together represent C4- or C5-alkylene 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-C6-alkyl-C1-C3-alkyl, or c) Ra, Rb and Rc together represent a hydrophobic group, and Rd represents hydrogen or C1-C4-alkyl, and A⁻

represents the anion of a pharmaceutically acceptable acid, as 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, as an alpha-amino acid compound of the formula

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 monoester of the formula

in which Ra represents a hydrophobic group and Y+represents the cation of a pharmaceutically acceptable base, or as an acid addition salt of a compound having a hydrophobic group Ra and an imidazoline, imidazolidine or hydrazino group as hydrophilic group.

53. Combination according to any of preceding claims,

wherein the said at least one third or one second amphipatic substance with biological activity, which can act as a drug, is a substituted 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-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-C4-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, preferably methyl, and k is the anion of a pharmaceutically acceptable acid, or a carboxylic acid salt of the formula 2 in which the hydrophobic group Ra can be an aliphatic hydrocarbon radical, which can be substituted by a monocyclic, aromatic hydrocarbon 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 monocyclic, 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.

54. Combination according to any of preceding claims,

wherein the said at least one third or one second amphipatic substance, which acts as a drug, is a substituted ammonium compound or the corresponding amino compound that can be converted into the ammonium compound by salt formation, such as 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, metopholine, etonitazene, ergotamine, dihydroergotamine, dihydroergocryptine, methysergide, lisuride, dimetotiazin, dizotifen, oxetoron, cyproheptadine, procaine, chloroprocaine, hydroxyprocaine, propoxycaine I oxy-buprocaine, propoxymetacaine, piridocaine, leucinocaine, butacaine p tetracaine, hydroxytetracaine, cornecaine, edan, piperocaine, cyclomethycaine, parethoxysaine, stadacain, cinchocaine, lidocaine, pyrrocaine, granocaine, butanilicaine, tolycaine, mepivacaine, bupivacaine, prilocaine, carticaine, dipiperidon, propicocaine, dyclonine, pramocaine, fomocaine, quinisocaine, profenamine, promethazine, periciazine, perimethazine, chlorpromazine, perphenazine, prochlorperazine, triflumpromazine, trifluoperazine, fluphenazine, thioridazine, mesoridazine, piperacetazine, acetophenazine, ethymemazine, dimethacrine, opipramol, clomipramine, imipramine, desimipramine, trimipramine, chloroprothixene, thiothixene, amitriptyline, nortriptyline, doxepin, thiepin, protriptyline, prothipendyl, femoxetin, citalopram, zimelidine, trebenzomin, viloxazine, nomifensine, femoxetin, tranylcygromine, pargyline, etryptamine, flurazepam, mescaline, Nalpha,Nalpha-dimethyl-tryptamine, bufotenine, psilocin, psilocylein, scopolamine, atropine, benzatropine, trihexyphenidyl, cycrimine, pridinol, biperidine, procyclidine, caramiphene, phenglutarimide, orphenadrine, chlor-phenoxamine, metixen, doxapram, amphetamine, methamphetamine, propylhexedrine, prolintane, fencamfamine, methylphenidol, pipradrol, phenmetrazine, diethylpropion, meclofenoxat, naftidrofuryl, dexamphetamine, phentermin, chlorphentermine, fenfluramine, amfepramone, phenmetrazine, phendimetrazine, tubocumarin, alcuronium chloride, gallamin triethiodide, hexacarbacholine bromide, pancuronium bromide, suxamethonium chloride, decamethonium bromide, scopolamine butyl bromide, bevonium methyl sulphate, valethamate bromide, methanteline bromide, camylofine, hexahydroadiphenine, adiphenine, fencarbamide, benzyclamine, ditaxol, chloroquine, tamoxifen, ethamoxytriphetol, phenbenzamine, tripelenamin, chlorpyramine, mepyramine, metaphenilene, metapyrilene, chloropyrilene, histpyrroclin, 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.

55. Combination according to any of preceding claims,

wherein the said at least one third or one second amphipatic substance takes the role of a drug as the substituted ammonium compound or as the corresponding amino compound that can be converted into the ammonium compound by salt formation, and is a compound selected from the group of the acid addition salts of antidepressants of the formula in which R1 represents lower alkyl, for example methyl, A represents the group N-ν

R1, oxygen or sulphur, and R2 represents hydrogen or cyano;

acid addition salts of antidepressants of the formula

in which R1 represents lower alkylamino-lower alkyl, for 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, 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.

56. Combina tion according to any of preceding claims, wherein the said at least one third or second amphipatic substance takes the role of a drug 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 formation, 1-(2R-2-hydroxy-3-methylaminopropyl)dibenzo[b,e]bicyclo[2.2.2]octadiene, and the 2R,S-isomeric mixture, maprotiline, benzoctamine, 3-methyldibenzo[2,3:

6,7]-oxepino[4,5-diazepine 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.

57. Combination according to any of preceding claims,

wherein the said at least one third or second amphipatic substance takes the role of a drug as the 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′

-pregnane, hydroxydione succinate sodium, 11,20-dioxo-3alpha-hydroxy-5alpha-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), PGF2alpha (dinoprost), 15 (S)-15-methyl-PGE2, 15 (S)-15-methyl-PGF2alpha (carboprost), (+)15 (Xi)-15-methyl-13,14-dihydro-11-deoxy-PGE1 (deprostil), 15 (S)-15-methyl-11-deoxy-PGE, (doxaprost), 16,16-dimethyl-PGE2, 17-phenyl-18,19,20-trinor-PGF2alpha, 16-phenoxy-17,18,19,20-tetranor-PGF2, or N-methylsulphonyl-16-phenoxy-17,18,19,20-tetranor-PGF2 alpha (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, cefinenoxime, ceftizoxime, cephalothin, cephradine, cefamandol, cephanone, cephapirin, cefroxadin, cefatrizine, cefazedonep ceftrixon, ceforanid, moxalactam, clavulanic acid, nocardicine A, sulbactam, aztreonam, thienamycin, chlorambucil or methotrexate.

58. Combination according to any of preceding claims,

wherein the said at least one third or second amphipatic substance, which takes to role of a drug, acts as an adrenocorticostatic, a β

-adrenolytic, an androgen an antiandrogen, an antiparasitic, an anabolic, an anaesthetic, an analgesic, an analeptic, an antiallergic, an antiarrhythmic, an antiarterosclerotic, an antiasthmatic, a bronchospasmolytic, an antibiotic, an antidrepressive, an antipsychotic, an antidiabetic, an antidot, an antiemetic, an antiepileptic, an antifibrinolytic, an anticonvulsive, an anticholinergic, an enzyme, a coenzyme or corresponding inhibitor, an antihistaminic, an antihypertonic, a biological inhibitor of drug activity, an antihypotonic, an anticoagulant, an antimycotic, an antimyasthenic, an agent against Morbus Parkinson or Morbus Alzheimer, an antiphlogistic, an antipyretic, an antirheumatic, an antiseptic, a respiratory analeptic or a respiratory stimulant, a broncholytic, a cardiotonic, a chemotherapeutic, a coronary dilatator, a cytostatic, a diuretic, a ganglium-blocker, a glucocorticoid, an antiflew agent, a haemostatic, a hypnotic, an immunoglobuline or its fragment, an immunologically active substance, a bioactive carbohydrate, a bioactive carbohydrate derivative, a contraceptive, an anti-migraine agent, a mineralo-corticoid, a morphine-antagonist, a muscle relaxant, a narcotic, a neurotherapeutic, a neuroleptic, a neurotransmitter or its antagonist, a small peptide, a small peptide derivative, an ophthalmic, a sympaticomimetic or a sympathicolytic, a para-sympaticomimetic or a para-sympathicolytic, a psoriasis drug, a neurodermitis drug, a mydriatic, a psychostimulant, a rhinologic, a sleep-inducing agent or its antagonist, a sedating agent, a spasmolytic, tuberculostatic, an urologic agent, a vasoconstrictor or vasodilatator, a virustatic, a wound-healing substance, or a combination of aforesaid agents.

59. Combination according to any of preceding claims,

wherein the drug content is between 0.1 rel.% and 60 rel.% compared to the total mass of all three said substances that form said extended surfaces.

60. Combination according to any of preceding claims,

wherein said at least one third or second substance is a low molecular weight immunomodulator.

61. Combination according to any of preceding claims,

wherein said at least one third or second substance is a bio-catalyst.

62. Combination according to any of preceding claims,

wherein said at least one third or second substance is a low molecular weight agonist or antagonist of some biological substance action.

63. Combination according to any of preceding claims,

wherein said at least one third or second substance is a co-enzyme.

64. Combination according to any of preceding claims,

wherein said at least one third or second substance is a hormone.

65. Combination according to any of preceding claims,

wherein said at least one third or second substance is a low to intermediate weight polypeptide with membrane destabilising properties.

66. Combination according to any of preceding claims,

wherein said at last one second substance is a cyclooxygenase or lipoxygenase inhibitor and at least one third substance is a non-ionic surfactant with solubility in 1-10 μ

M range that preferably belongs to the class of sorbitane-polyoxyethylene-alkyl or -alkylene esters or else is a polyoxyethylene-alkyl or -alkylene ether.

67. The use of a combination of substances according to any of preceding claims, in drug carriers, drug depots, or for other kind of medicinal or biological application by providing the extended surfaces in the form of membranes formed by the at least one first substance, the at least one second and the at least one third substance, which together surround miniature droplets, wherein the substance with biological activity, being a drug, is mainly associated with said droplet surface or else is mainly incorporated into the droplet and then carried by the droplet to the place where the drug is intended to act.

68. The use of a combination of substances according to any of preceding claims for the manufacture of a preparation for the transport of an active ingredient, which can be one of the three amphipatic components, especially for biological, medical, immunological, or cosmetic purposes, into and through the skin of warm blood creatures.

69. A method of preparing a combination according to any of preceding claims in the form of a formulation of a biologically, cosmetically and/or pharmaceutically active agent, comprising the steps of

selecting the at least one first and the at least one second substance which together form extended surfaces, when in contact with said medium, such that said extended surfaces formed by the at least one first and the at least one second substance are more adaptable than the at least one first substance alone and the surfaces formed by the at least one second substance alone form small aggregates;

alternatively

selecting the at least one first and the at least one third substance which together form extended surfaces, when in contact with said medium, such that said extended surfaces formed by the at least one first and the at least one third substance are more adaptable than the at least one first substance alone and the surfaces formed by the at least one third substance alone form small aggregates, if this substance self-aggregates; and

generating said surface-forming combination from at least one first, at least one second, and at least one third substance, such that the surface of resulting at least three component combination is even more adaptable than the surface prepared from at least one first and one second substance alone or of the surfaces formed by the at least one first and one third substance alone, bringing the combination of at least two or all three said substances into suspension by means of controlled mechanical fragmentation, in the presence of or before being mixed with the at least one third substance, such that said third substance is incorporated at least partly in said extended surface formed by controlled mechanical fragmentation to obtain final preparation.

70. The method according to any of preceding claims,

wherein said means of controlled mechanical fragmentation includes on filtration, pressure change or mechanical homogenisation, shaking, stirring, or mixing.

71. The method according to any of preceding claims,

wherein the liquid medium suspension characteristics correspond to any one of claims 1 to 65.

72. The method according to any of preceding claims,

wherein said active agent is selected from the group comprising anti-diabetic agents, growth factors, immunomodulators, enzymes, recognition molecules, adrenocorticostatics, adrenolytics, androgens, antiandrogens, antiparasitics, anabolics, anaesthetics, analgesics, analeptics, antiallergics, antiarrhythmics, antiarteroscierotics, antiasthmatics, bronchospasmolytics, antibiotics, antidrepressiva, antipsychotics, antidots, antiemetics, antiepileptics, antifibrinolytics, anticonvulsiva, anticholinergics, enzyme, coenzymes or corresponding inhibitors, antihistaminics, antihypertonics, biological inhibitors of drug activity, antihypotonics, anticoagulants, antimycotics, antimyasthenics, agents against Morbus Parkinson or Morbus Alzheimer, antiphlogistics, antipyretics, antirheumatics, antiseptics, respiratory analeptics or respiratory stimulants, broncholytics, cardiotonics, chemotherapeutics, coronary dilatators, cytostatics, diuretics, ganglium-blockers, glucocorticoids, antiflew agents, haemostatics, hypnotics, immunologically active substances, contraceptives, anti-migraine agents, mineralo-corticoids, morphine-antagonists, muscle relaxants, narcotics, neurotherapeutics, neuroleptics, neurotransmitters or their antagonists, peptides, peptide derivatives, opthalmics, sympaticomimetics or sympathicolytics, para-sympaticomimetics or para-sympathicolytics, anti-psoriasis drugs, neurodermitis drugs, mydriatics, psychostimulants, rhinologics, sleep-inducing agents or their antagonists, sedating agents, spasmolytics, tuberculostatics, urologics, vasoconstrictors or vasodilatators, virustatics, wound-healing substances, or a combination of aforesaid agents.

73. The method according to any of preceding claims,

wherein said at least three amphiphilic substances are either used as such, or dissolved in a physiologically compatible polar fluid, comprising water or water-miscible fluids, or in a solvation-mediating agent, together with a polar solution.

74. The method according to any of preceding claims,

wherein the said polar solution contains at least one surfactant or surfactant-like amphipat, which destabilises bilayer membrane, and at least one more membrane destabilising, biologically active ingredient or an additional surfactant.

75. The method according to any of preceding claims,

wherein the formation of said surfaces is induced by substance addition into a fluid phase, evaporation from a reverse phase, by injection or dialysis, or with the aid of mechanical stress.

76. The method according to any of preceding claims,

wherein the formation of said surfaces is induced by filtration, the filtering material having pores diameters between 0.01 μ

m and 0.8 μ

m, the preferred choice of pore diameter being dependent on the desired final aggregate dimensions.

77. The method according to any of preceding claims,

wherein several filters are used sequentially or in parallel.

78. The method according to any of preceding claims,

wherein said agents and carriers are made to associate, at least partly, after formation of said extended surfaces.

79. The method according to any of preceding claims,

wherein said extended surfaces, with which the agent molecules are allowed to associate, are prepared just before the application of the formulation, if convenient from a suitable concentrate or a lyophylisate.

80. A container comprising the pharmaceutical composition based a combination of substances according to any preceding claim.

81. A package comprising at least one container comprising the pharmaceutical composition based on a combination of substances according to any preceding claims.

82. A method for generating a therapeutic effect on a warm blood creature by applying a pharmaceutical composition based on a combination of substances according to any of previous claims onto or into such living creature body.

83. The method according to any of preceding claims,

wherein different administration volumes are selected to control the applied medicament dose and the outcome of therapeutic application.

84. The method according to any of preceding claims,

wherein a suspension of drug-free aggregates is loaded with the drug to be associated therewith during the day prior to an administration, preferably 360 min, more preferably 60 min and even more preferably 30 min before administering the resulting formulation in or on the body.

85. The method of any of preceding claims,

characterised in that at least one dose of the pharmaceutical composition with therapeutic activity is administered.

86. The method according to any of preceding claims,

wherein the flux of penetrants that carry a drug through the various pores in a well-defined barrier is determined as a function of a suitable driving force or a pressure acting across the barrier and the data are then conveniently described by a characteristic curve which, in turn, is employed to optimise the formulation or application further.

87. The method according to any of preceding claims,

wherein the characteristic, e.g. penetrability vs. pressure, curve is analysed in terms of eq. (*) or alike.

88. The combination of any of preceding claims, wherein the adaptability of extended surface aggregates comprising all three said amphipatic components exceeds by at least 20% or by at least twice the standard deviation of a typical measurement, whichever is smaller, the adaptability of the extended surface aggregates comprising the at least one first and the at least one second amphipatic component, used at the corresponding concentrations, or the adaptability of the extended surface comprising the at least one first and the at least one third amphipatic component, used at the corresponding concentrations, whichever is smaller.

89. The combination of any of preceding claims, wherein the adaptability of extended surface aggregates comprising all three said amphipatic components exceeds by at least 30% the adaptability of the extended surface aggregates comprising the at least one first and the at least one second amphipatic component, used at the corresponding concentrations, or the adaptability of the extended surface comprising the at least one first and the at least one third amphipatic component, used at the corresponding concentrations, whichever is smaller.

90. The combination of any of preceding claims, wherein the total concentration of said at least one second and said at least one third compound in the ESAs comprising all three said amphipatic components is equal to or less than the concentration of said at least one second compound in the ESAs comprising at least one first and at least one second compound and the corresponding concentration of the at least one first compound.

91. The combination of any of preceding claims, wherein the total concentration of said at least one second and said at least one third compound in the ESAs comprising all three said amphipatic components is equal to or less than the concentration of said at least one third compound in the ESAs comprising at least one first and at least one second compound at the corresponding concentration of the at least one first compound.

92. The combination of any of preceding claims, wherein the adaptability is expressed as the inverse value of the p* value corresponding to a predefined fraction of P_max-value, which is often selected around 60% and preferably is 57% of P_max-value.

2. A combination of at least one first (membrane forming component MFC), at least one second (membrane destabilising component MDC), and at least one third (membrane destabilising component MDC) amphipatic component suspended in a suitable liquid medium in the form of mixed amphipat aggregates with extended surface (ESAs) with one or a few mixed amphipat coating(s), which are preferably bilayer like, wherein the

said at least one first substance has a tendency to self aggregate and is at least 10-times less soluble in said liquid medium than said at least one second and said one third substance, allowing the first to form extended surfaces,

said at least one second substance is at least 10-times more soluble than said at least one first substance in said liquid medium and, on its own, tends to form or supports the formation of surfaces that are at least 2-times less extended than the surfaces containing the at least one first substance alone,

said at least one third substance being also at least 10-times more soluble in said liquid medium than the first substance and optionally forms self-aggregates with aggregation number at least 10-times smaller than that of self-aggregates of said first substance;

and

said extended surfaces comprising said at least one first, at least one second and at last one third substance, in equilibrium, have at least 50% greater surface than the surfaces formed by the at least one second or one third substance alone, at the same concentration and, in case, after adjustment for the physico-chemical effects of the absence of said first amphipatic compound (MFC)

for a preparation for application, administration or transport of at least one active ingredient, which can be one of the three amphipatic components, especially for medicinal or biological purposes, into and through barriers and constrictions, such as the skin of warm blood creatures or the like.

3. Extended-surface aggregates (ESAs) comprising at least one first (membrane forming component, MFC), at least one second (membrane destabilising component, MDC), and at least one third (membrane destabilising component, MDC), all of which are amphipatic, suspended in a suitable liquid medium, which permits said ESAs to permeate barriers with the pores with at least 40% smaller radius than the average ESAs radius, as measured after the ESAs have permeated the barrier pores and assuming spherical ESAs geometry.

4. Preparation based on a combination of at least one first (membrane forming component MFC), at least one second (membrane destabilising component MDC), and at least one third (membrane destabilising component MDC) amphipatic component suspended in a suitable liquid medium in the form of corresponding mixed amphipat aggregates with an extended surface (ESAs) with one or a few, preferably bilayer-like, mixed amphipat coating(s), wherein said MFC alone forms extended-surface aggregates with aggregation number of at least 5000, and preferably more than 10.000, and both MDCs alone and the combination of both MDCs form smaller aggregates with no substantially extended surface and aggregation number below 5000, and preferably below 1000 in contact with said suitable liquid medium.