HK1021622B - Preparation for the transport of an active substance across barriers - Google Patents

Description

The invention relates to the use of preparations for the non-invasive application of active substances in the form of small droplets of liquid suspended in a liquid medium with a membrane-like envelope of one or a few molecular layers containing an active substance and particularly suitable for transporting the active substance through barriers, such as natural permeability barriers and constrictions in skin, mucous membranes, organs and the like.

The invention also relates to a method for the manufacture of such preparations, in particular for the non-invasive administration of active substances.

The application of active substances is often restricted by natural barriers such as skin, which prevent the adequate administration of active substances, as they are too impermeable to active substances. For example, due to the skin permeation barrier, most common therapeutics must be administered either orally or parenterally (i.v., i.m., i.p.). Intrapulmonary and intranasal applications of aerosols, the use of rectal suppositories, the application of mucosal gels, ocular preparations, etc. can only be implemented at certain sites and not with all active substances.

Noninvasive applications of active substances capable of penetrating such permeability barriers would be beneficial in many cases. e.g. in humans and animals, percutaneous application of such preparations would protect the administered active substances from decomposition in the gastrointestinal tract and, if necessary, result in modified agent distribution in the body; it can influence the pharmacokinetics of the drug and allow for both frequent and simple noninvasive treatment (Karzel K., Liedtke, R.K. (1989) Medicines. Research/Drug Res. 39, 1487 - 1491). In plants, improved penetration by the plant or in the cuticle could significantly reduce the concentration of the active substance required for an elevated effect and also reduce the environmental impact (E.E. Cutler, The Academic, C.E.C.E., 23 pp. 25-21).

Efforts to influence skin permeability through appropriate measures have been widely discussed (see e.g. Karzel and Liedtke, op. cit.). Particularly noteworthy are e.g. jet injection (Siddiqui & Chien (1987) Crit. Rev. Ther. Drug. Carrier. Syst. 3, 195-208). the use of electric fields (Burnette & Ongpipattanakul (1987) J. Pharm. Sci. 76, 765-773) or the use of chemical additives, such as solvents or surfactants.

The most well-known method of increasing the penetration of the active substance through the skin or mucous membrane is the use of penetration enhancers, which include non-ionic substances (long-chain alcohols, surfactants, zwitterionic phospholipids), anionic substances (especially fatty acids), cationic long-chain amines, sulfoxides and various amino derivatives, as well as amphoteric glycinates and betaines.

An overview of the measures used to increase the penetration of the active substance by the plant cuticles is summarized in Price's (1981, op. cit.).

The penetration enhancers used exclusively in occlusive applications up to now increase the penetration capacity at the permeability barrier of the skin or mucous membrane surface by increasing the fluidity of a part of the lipids in this barrier. When chemical penetration enhancers were used, it was usual to add them simply to the active mixture; however, in the case of human skin, additives were sometimes also applied in advance, in the form of an organic solution. This presentation form was combined with the principles of action of additives studied and discussed so far: it was generally assumed that the increased penetration of the surface of the agent was based on the softening (fluidization) of the skin (Guerrier et al., 1987); and, on the other hand, on the softening (fluidization) of the skin (Guerrier et al., 1987; J. Green et al. 106, 106, 106, 108, 108).

Proposals that deviate from these concepts, such as the epidermal application of lipid suspensions, have so far yielded little improvement.

The percutaneous use of lipid-based carriers, the liposomes (Patel, Bioch. Soc. Trans., 609th Meeting, 13, 513-517, 1985, Mezei, M. Top. Pharm. Sci. (Proc. 45th Int. Congr. Pharm. Sci. F.I.P.,) 345-58 Elsevier, Amsterdam, 1985) discussed by several authors was mainly aimed at influencing the kinetics of the active substance.

The Japanese patent application JP 61/271204 A2 [86/271204] addressed the use of liposomes by using hydroquinone glucosidal as a stability enhancer in a similar sense.

As an improvement, the use of active substance-laden lipid vesicles together with a gel-forming agent in the form of transdermal patches was proposed in WO 87/1938 A1. This extended the duration of action but did little to increase the penetration capacity of the active substance.

In addition, carrier formulations have been found which are suitable for penetration into and through permeability barriers, and the results of Gesztes and Mezei have been dramatically exceeded for the first time by a special formulation which has filtered detergent-containing lipid vesicles (liposomes) with a declared optimal lipid/tensidic content of 1-40/1, which in practice usually have a 4/1 ratio.

It was also found that all such media are suitable for penetration into and through the permeability barriers, and are sufficiently elastic to penetrate through the constrictions of the barrier, e.g. the skin.This is particularly the case if the media themselves build up a gradient on the permeability barrier after application, as in this case they tend to spontaneously penetrate the permeability barrier.The patent applications DE 41 07 152 and DE 41 07 153 describe for the first time carriers, hereinafter referred to as transferases, which are suitable for the active substance by virtually any permeable transport barrier.

Transferases differ from liposomes and other related vectors previously described for topical use in several basic properties. Transferases are generally much larger than conventional measles-like vector formulations and are therefore subject to different diffusion laws. Thus, permeability is not a linear function of the driving pressure, as with liposomes, i.e. in contrast to liposomes or other similar vector systems known, permeability decreases at pressure increases that are either sub-proportional or non-linear. Furthermore, substances introduced by transferases by means of restriction therapy can reach almost 100% of the maximum attainable biological or therapeutic thrombopoietic potential in humans.

The key condition for the increased penetration of the transferases against liposomes or other similar known vectors was the presence of a marginal active substance which would optimise the approach to the solubilisation limit of the transferases (i.e. a marginal active substance which would completely destabilise the transferases) so that they are sufficiently elastic to penetrate the constrictions in the barrier, e.g. in the skin.

It would be highly desirable, therefore, that the formulation of such highly permeable preparations should not be bound by the content ranges mentioned.

It is therefore a task of the invention to specify transferases that either have no or are distant from the point of solubilization for the application of active substances that allow their rapid and effective transport through barriers and constrictions.

The purpose of the invention is further to make transferases available for transport of the active substance through human, animal and plant barriers, which allows for improved availability of the active substance at the site of action.

The purpose of the invention is further to indicate a method for the production of such transferases for the transport of active substances.

The characteristics of independent claims are used to solve this problem.

The sub-claims indicate the advantages of the design.

Surprisingly, it was found that transferase preparations can also be prepared for the application or transport of at least one active substance, particularly for medical and biological purposes, in and through natural barriers and structures such as skin and the like, in the form of liquid droplets which can be suspended in a liquid medium, with a membrane-like shell of one or a few layers of amphiphiphilic carrier substance, the carrier substance comprising at least two (physicochemically) different amphilic components which differ in their solubility in the suspension medium of the transferase (clear water) by a factor of at least 10 and whose solubility in soluble solvents is less than 0.1% when the soluble solvent is not soluble or when no soluble solvent is present at the solvent concentration point, so that the solubility of these components is achieved at the point of dissolving the solvent, regardless of the solvent content.

The preparations of the invention, hereinafter referred to as transferases, can be prepared from any amphiphilic component with sufficiently different solubility. This condition is satisfied if the solubilities of the individual carrier components of the transferase in the suspension medium differ by at least a factor of 101 (and up to 107); this condition ensures that the membrane-like envelope of the resulting transferases has a graduated deformability under the influence of a gradient, for example on an intact natural barrier such as the skin. This property allows the transferases to penetrate into the solution by means of the constraints in the permeability gradient.

The ability of the preparations of the invention to permeate through constriction is at least 0.01 per cent, but preferably more than 1 per cent of the permeability of small, essentially unimpeded molecules.

The term solubility, as used herein, refers to so-called real solutions according to current knowledge (but without having to be bound by a theoretical-scientific definition), but at any rate, when a specific limit concentration is reached, a solubility limit is observed, defined by the formation of precipitation, crystal formation, suspension formation, or molecular aggregates such as mycellae.

The transferases of the invention differ significantly from the transferases described above; in particular, the transferases of the present application differ from known transferases in that the transferases can be formed from combinations of any component, regardless of their solubilization capacity.

In addition, the transferomers of the invention have an even better stability than the known transferomers (see patent applications WO 92703122 and EP 475 160) because the transferomers are not close to the solubilization point.

Figure 1 shows the decrease in permeation resistance at a barrier as a function of the concentration of the marginal active substance in relation to the approach to the solubilization point for transferases described in the state of the art (but not reaching this solubilization point).

Figure 2 shows the decrease in the permeation resistance at a barrier at the transferring transferring solvent according to the invention, depending on the component concentration as it approaches a theoretical solubilization point which cannot be reached in practice.

Figure 2 shows clearly that for the component systems of the transferases of the invention, no solubilization point exists or the solubilization point is still far away when the maximum permeability is reached.

The transferases of the invention thus provide an elegant, uniform and generally useful way of transporting various active substances in or through permeability barriers. e newly discovered active substance carriers are suitable for use in human and veterinary medicine, dermatology, cosmetics, biology, biotechnology, agricultural technology and other fields.

A transferome is also characterised by its ability to penetrate and/or diffuse through and/or into permeability barriers under the action of a gradient, and to transport substances, in particular active substances.

The transferome is composed of several to many molecules, which form a physical-chemical, physical, thermodynamic and often functional unit. The optimal transferome size is a function of the barrier characteristics. It also depends on the polarity (hydrophilia), mobility (dynamics) and charge as well as the elasticity of the transferome.

For dermatological applications, the transferomes of the invention are preferably used in the range of 50 to 10,000 nm, frequently 75 to 400 nm, and particularly frequently 100 to 200 nm.

For applications on plants, relatively small transferases, predominantly of less than 500 nm in diameter, are used as appropriate.

The vesicle radius of the preparation droplets (transfersomes) is approximately 25 to 500, preferably 50 to 200 and especially preferably 80 to 180 nm.

For transfer enzymes of the invention from any amphiphilia, one or more components with a water solubility between 10-10 M and 10-6 M and one or more components with a water solubility between 10-6 M and 10-3 M are preferably combined; alternatively, the combined amphiphilic components may be allocated to each other also by their HLB values, with the difference between the HLB values of both components preferably up to 10, often between 2 and 7 and particularly often 3-5;

The penetration capacity of the transfer particles according to the invention can be determined by comparison measurements with reference particles or molecules. The reference particles used are significantly smaller than the constrictions in the barrier and thus maximally permeable. Preferably, the transfer particles permeation rate by a test barrier (PTtransf.) should be smaller than the permeation rate of the comparator PRefer (e.g. water) when the barrier itself is the destination, so as to differ by no more than a factor between 10-5 and 10-3. If relatively uniform and slow transport through the barrier is desired, the specified material should be 10-4 and 1. Maximum penetration capacity is given when the PT/PTR is greater than 10-2. These data refer to transfers of proportional size which may vary by a factor of less than 4 and are greater than 4 W/m2.

The transferases referred to in these applications may consist of one or more components. The most commonly used is a mixture of basic substances. Suitable basic substances include lipids and other amphiphiles, as well as hydrophilic liquids, which can be mixed with the active substance molecules in certain ratios which depend both on the choice of substances and their absolute concentrations.

Generally, the preparations contain at least two amphiphilic components of different solubility, forming a membrane-like envelope around a droplet of hydrophilic liquid, with the active substance contained in the membrane-like envelope, e.g. a double membrane and/or in the hydrophilic liquid.

If the transferases are not sufficiently deformable on their own and their permeability is to be achieved by the addition of marginal active substances, the concentration of these substances is less than 0.1% of the amount that would be required for the transferases to be soluble or is not at all soluble within the concentration range of practical relevance.

The transferases of the invention are suitable for transporting the active substance through almost any permeation barrier, e.g. for percutaneous drug application. They can transport water-soluble, amphiphilic or fat-soluble agents and achieve different penetration depths depending on their composition, application amount and form. The special properties that make a carrier a transferase can be achieved by both phospholipid-containing vesicles and other amphiphilages.

The following definitions apply: The following are the lipids:

A lipid in the sense of the present invention is any substance having fatty or fat-like properties, usually having an extended apolar residue (the chain, X) and usually also a water-soluble polar hydrophilic part, the head group (Y), and having the basic formula 1. ${\text{X - Y}}_{\text{n}}$ In this sense, all amphiphiles, such as glycerides, glycerophospholipids, glycerophosphinolipids, glycerophosphonolipids, sulfolipids, sphingolipids, isoprenoid lipids, steroids, sterols or sterols, and carbohydrate lipids can be generally referred to as lipids.

For example, a phospholipid is a compound of formula 2: R4 is also a short alkyl substituted by a tri-short chain alkylammonium, e.g. trimethylammonium, or an amino short chain alkyl, e.g. 2-trimethylammoniumethyl (cholinyl).

A lipid is preferably a substance of formula 2 wherein n = one, R1 and R2 are hydroxyacyl, R3 hydrogen and R4 2-trimethyl-ammonioethyl (the latter corresponding to the phosphatidylcholine head group), 2-dimethylammonioethyl, 2-methylammonioethyl or 2-aminoethyl (the corresponding phosphatidylethanolamine head group).

One such lipid is natural phosphatidylcholine (also called lecithin), which can be obtained from eggs (rich in arachidonic acid), soybeans (rich in C-18 chains), coconuts (rich in saturated chains), olives (rich in monounsaturated chains), saffron (saffron) and sunflowers (rich in n-6 linoleic acid), flaxseeds (rich in n-3 linoleic acid), whale fat (rich in monounsaturated n-3 chains), night candle or primrose (rich in n-3 chains).

In addition, synthetic phosphatidylcholine (R4 corresponds to 2-trimethylammoniumethyl in formula 2) is preferred as lipids, synthetic phosphatidylethanolamine (R4 corresponds to 2-aminoethyl), synthetic phosphatidyl acids (R4 is one proton) or their esters (R4 corresponds to e.g. a short-chain alkyl, such as methyl or ethyl), synthetic phosphatidylserine (R4 corresponds to L or D-serine), or synthetic phosphatidyl polyoxy alcohols, such as phosphatidylinositol, phosphatidylglycerol (R4 corresponds to L or D-glycerol), synthetic phosphatidylphosphatidylserine (R4 corresponds to a proton) or their esters (R4 corresponds to a short-chain alkyl, such as methyl or ethyl), synthetic phosphatidylserine (R4 corresponds to L or D-glycerol), or synthetic phosphatidylserine (R4 corresponds to a short-chain alkyl, such as methyl or ethyl), or synthetic phosphatidylserine (R4 corresponds to a short-chain alkyl, such as methyl or ethyl, or ethyl, or ethyl, or ethyl, or ethyl, or eth, or eth, or eth, or eth), or phosphatidyl, or phosphatidyl, or phosphatidyl, or phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl, phosphatidyl

A suitable lipid for the purposes of this invention is also a lipid of formula 2, where n = 1, R1 is an alkenyl residue, R2 is an acyl amidoresist, R3 is hydrogen and R4 is 2-trimethylammonioethyl (choline residue).

A suitable lipid is also a lysophosphatidylcholine ana-log such as 1-lauroyl-1,3-propandiol-3-phosphorylylcholine, a monoglyceride such as monoolein or monomyristine, a cerebroside, ceramid polyhexoside, sulfatide, sphingoplasmalogen, a ganglioside or a glyceride which does not contain a free or esterified phosphoryl or phosphonyl group or a phosphonyl group in 3 positions. Such a glyceride is, for example, a diacylglyceride or 1-al-hydroxyyl-1-acylglyceride with adjacent acyl groups or alkenes in which the 3-hydroxy group is separated by a carbon called a carbonyl group, such as a galaxy-Brestylglycerol in a monogalactos.

Lipids with desired head or chain group properties can also be biochemically produced, e.g. by phospholipases (such as phospholipase A1, A2, B, C and especially D), desaturases, elongases, acyl transferases, etc. from natural or synthetic precursors.

A suitable lipid is also any lipid which is contained in biological membranes and which can be extracted by means of a polar organic solvent, e.g. chloroform. Such lipids include, in addition to the lipids already mentioned, for example, steroids, e.g. estradiol, or sterols, e.g. cholesterol, beta-cytosterine, desmosterine, 7-keto-cholesterine or beta-cholestanol, fat-soluble vitamins, e.g. retinoids, vitamins, e.g. vitamin A1 or A2, vitamin E, vitamin K, e.g. vitamin K1 or K2 or vitamin D1 or D3, etc.

The less soluble amphiphilic component preferably includes or includes a synthetic lipid such as myristoleoyl, palmitoleoyl, petroselinyl, petroselaidyl, oleoyl, elaidyl, cis- or trans-vaccenoyl, linoyl, linolenyl, linolaidyl, octadecatetraenoyl, gondolyl, eicosaenoyl, eicosadienoyl, eatrienoyl, arachidyl, cis- or trans-docosaenoyl, docosaenoyl, docosaenoyl, petroselinyl, lauroyl, tri-decanoyl, myristoecyclohexanol, pentanoyl, non-cetoyl, stearyl, stearyl, or diethyl glycyl glycyl, respectively, and a corresponding glycolipid or other diethyl or diethyl ketone derivative.

The more soluble amphiphilic component is often derived from the less soluble components listed above and substituted and/or complexed with, and/or associated with, a butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl or undecanoyl substituent or several independently selected substituents or another substance suitable to improve solubility to increase solubility.

A diacyl or dialkylglycerophosphoethanolamine polyethoxyl derivative, a didecanoylphosphatidylcholine or a diacylphospholigomalbionamide is also an appropriate lipid.

A lipid within the meaning of the present invention is any other substance (e.g. a poly- or oligo-aminoside) which has a low or at least partial solubility in polar media.

All surfactants as well as asymmetrical, and therefore amphiphilic, molecules or polymers, such as some oligo- and polycarbohydrates, oligo- and polypeptides, oligo- and polynucleotides, many alcohols or derivatives of such molecules, belong to this category.

The polarity of the 'solvents', surfactants, lipids or active substances used depends on the effective relative hydrophilia/hydrophobia of the molecule concerned, but also depends on the choice of other system components and the boundary conditions in the system (temperature, salinity, pH, etc.). Functional groups, e.g. double bonds in the hydrophobic residue that attenuate the hydrophobic character of this residue, increase polarity; elongation or space-consuming substituents in the hydrophobic residue, e.g. in the aromatic residue, decrease the polarity of a substance. Gelated or polar groups in the hydrophobic group, when raised to the same temperature, usually have a higher polarity and have a direct effect on the polarity between the components of the solution and the lipophilic B-like lipids.

As highly polar substances, all compounds which are listed as rand-active in EP patent application 475 160 are particularly suitable.

The following shall be added:

The transferases of the invention are suitable for the application of a wide variety of active substances, in particular for therapeutic purposes, for example, in particular, preparations of the invention may contain all the active substances mentioned in the EP patent application 475 160.

The preparations of the invention may also contain as active substance an adrenocorticostatic, β-adrenolytic, androgen or antiandrogen, antiparasitic, anabolic, anaesthetic or analgesic, analeptic, antiallergic, antiarrhythmic, antiarterosclerotic, antiasthmatic and/or bronchospasmolytic, antibiotic, antidepressant and/or antipsychotic, anti-diabetic, anti-hydrogen, antiemetic, anti-epileptic, anti-fibrinolytic, anti-convulsant, anticholinergic, anticoagulant, antihypertensive or an equivalent derivative thereof, an antihypertensive, an anti-neuropathic, an anti-hypertensive, an anti-stimulant, an anti-potentially active biological agent, an anti-stimulant, an anti-blood, an anti-inflammatory, an anti-corrective, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti-psychotic, an anti

Preferably, the active substance is a non-steroidal anti-inflammatory such as diclofenac, ibuprofen or a lithium, sodium, potassium, cesium, rubidium, ammonium, monomethyl, dimethyl, trimethyl ammonium or ethyl ammonium salt thereof.

In addition, preparations of the invention may contain as active substance a substance which affects the growth of living organisms, a biocide, such as an insecticide, pesticide, herbicide, fungicide, or a lure, in particular a pheromone.

Preparations of the invention may contain as a less polar component a physiologically compatible lipid, preferably of the phospholipid class, preferably of the phosphatidylcholine class, where the active substance, e.g. ibuprofen, diclofenac or a salt thereof, being the more soluble component, may be added with an addition of less than 10% by weight, if applicable, in relation to the total composition of the preparation of another soluble component, and where the concentration of the more soluble components (n) is typically between 0,01 and 15% by weight, preferably between 0,1% and 10% by weight, and preferably between 0,5% and 3% by weight, and the total lipid concentration is between 0,005% and 40% by weight, preferably between 0,5% and 15% by weight, and preferably between 10% and 1% by weight.

The preparations of the invention may also include consistency-forming agents such as hydrogels, antioxidants such as probucol, tocopherol, BHT, ascorbic acid, desferroxamine and/or stabilizers such as phenol, cresol, benzyl alcohol and the like.

Unless otherwise specified, all declared substances, surfactants, lipids, active substances or additives with one or more chiral carbon atoms may be used either as racemic mixtures or as optically pure enantiomers.

The following shall be applied:

In the case of permeation barriers, the transport of the active substance can be handled by such transferases which fulfil the following basic criteria:The transferases should feel or build up a gradient which drives them into or over the barrier, e.g. from the body surface into and under the skin, from the leaf surface into the leaf interior, from one side of the barrier to the other;The permeation resistance felt by the transferases in the barrier should be as small as possible in relation to the driving force;The transferases should be able to permeate into and/or through the barrier without uncontrolled loss of the contained active substances.

In addition, the transferases should preferably allow control over the distribution of the active substance, the effects of the active substance and the timing of the action; they should be able to move and/or catalyze the transport of material to and from the barrier if necessary; and, last but not least, they should influence the range and depth of action and, in favourable cases, the type of cells, tissues, organs or system segments to be reached or treated.

The chemical gradients are particularly suitable for biological applications, such as the (de) hydration pressure (humidity gradient) or a concentration difference between the application and the site of action; electric or magnetic fields and thermal gradients are also of interest in this respect.

To satisfy the second condition, the transferases must be sufficiently 'thin-liquid' at the microscopic scale, i.e. have a high mechanical elasticity and deformability and a sufficiently low viscosity, only then can they pass through the constrictions within the permeability barrier.

The permeation resistance decreases with the size of the carrier, but the driving force is often dependent on the size of the carrier; under pressure independent of size, this force typically decreases with size.

The choice of carrier substances, active substances and additives, as well as the amount or concentration of carrier applied, also play a role. Low dosage usually results in a superficial treatment: substances which are poorly water soluble usually remain in the apolar region of the permeability barrier (e.g. in the membranes of the epidermis); well-soluble agents which diffuse easily from the carriers may have a different distribution from the carriers; for such substances the permeability of the transferase membrane is therefore also important. Substances which tend to pass from the carriers into the barrier of a carrier have a locally variable composition, etc. These correlations should be considered before and during each application.The following rule of thumb can be used to find conditions under which the simple carrier vesicles become transferases. First, two or more amphiphilic components are combined, differing in their solubility in the intended medium of suspension of the transferred transferred somates, usually water or another polar, mostly aqueous medium, by a factor of 10 to 107, preferably 102 and 106 and preferably 103 to 105, with the less soluble component having a solubility of 10 to 10 and the more soluble component having a solubility in the range of 10 to 6 and 10 to 3 M. The solubility of the resulting components, if not known from the general reference works,Err1:Expecting ',' delimiter: line 1 column 462 (char 461)The penetration capacity of the transfer atoms of the invention can be determined by comparative measurements with reference particles or molecules. The reference particles used are significantly smaller than the constrictions in the barrier and thus maximally permeable. Preferably, the rate of blood-transfer permeation through a test barrier (PTf) and the rate of permeation of the comparator substances (e.g. water barrier) should differ by a factor of between 10 and 5 when the reference location is not more than 10-3 and the reference location is not more than 10-5

This application discusses relevant properties of transferases as carriers for the lipid vesicles. Most examples refer to the carriers from phospholipids, for example, but the general validity of the conclusions is not limited to this class of carriers or molecules. The lipid vesicle examples merely illustrate the properties required for penetration through the permeability barriers, such as skin. The same properties also allow carrier transport through the epidermis of animals or humans, mucous membranes, plant cuticula, inorganic membranes, etc.

The probable reason for the spontaneous permeation of transferases through the pores in the corneal layer is that they terminate on one side in an aqueous compartment, the subcutis, and the transferases are driven by osmotic pressure.

Depending on the amount of vesicles, percutaneous application can lead to the subcutaneous entry of lipid vesicles, where the active substances are either locally released, proximal enriched or passed on to the lymphatic or blood vessels and distributed throughout the body, depending on the size, composition and formulation of the carriers or agents.

Sometimes it is appropriate to adjust the pH of the formulation immediately after manufacture or immediately before application. Such adjustment is intended to prevent the destruction of the systemic components and/or the active substance carrier under the initial pH conditions and to ensure the physiological compatibility of the formulation. For neutralization, physiologically compatible acids or bases or buffer solutions with a pH of 3-12 are usually used, preferably 5 to 9, and more commonly 6-8 depending on the purpose and location of application. Physiologically acceptable acids are for example dilute mineral acids such as dilute hydrochloric acid, sulphuric acid or phosphoric acid, or organic acids such as alkanic acid, phosphoric acid, phosphoric acid, phosphoric acid, phosphoric acid, phosphoric acid, phosphoric acid, phosphoric acid, etc.

The production temperature is usually adapted to the substances used and is usually between 0 and 95 °C for aqueous preparations. Preferably, the temperature range is between 18 and 70 °C; particularly for liquid-chain lipids, the temperature range is between 15 and 55 °C, for regular-chain lipids, between 45 and 60 °C. Other temperature ranges are possible for non-aqueous systems or for preparations containing or produced in cryopreservatives or heat-containing situations.

If the sensitivity of the system components so requires, the formulations can be stored cool (e.g. at 4°C). They can also be produced and stored in an inert gas, e.g. nitrogen atmosphere. The storage life can be further extended by using substances without multiple bonds and by drying and using dry substance which is only dissolved and processed in situ, in particular the transferomers can be prepared from a concentrate or lyophilisate just before application.

In most cases the carrier is applied at room temperature, but applications at lower or higher temperatures with synthetic substances at even higher temperatures are quite possible.

The production of a transferase suspension may be carried out by means of mechanical, thermal, chemical or electrical energy supply, such as homogenization or stirring.

The filter material used for this purpose should have a pore size of 0,01 to 0,8 μm, in particular 0,05 to 0,3 μm and preferably 0,08 to 0,15 μm, where necessary using several filters in succession.

The preparations may be prepared in advance or at the site of application, as described, for example, in P 40 26 833.0-43 or by several examples in the manual "Liposomes" (Gregoriadis, G., Hrsg., CRC Press, Boca Raton, Fl., Volumes 1-3, 1987), in the book "Liposomes as drug carriers" (Gregoriadis, G., Hrsg., John Wiley & Sons, New York, 1988), or in the laboratory manual "Liposomes. A Practical Approach" (New, R., Oxford-Press, 1989). If necessary, an active substance suspension may be diluted or concentrated (e.g. by centrifugation or ultrafiltration) immediately before use or mixed with other additives for optimum displacement of the drug, but the possibility of a displacement of the drug should be excluded.

The transferases referred to in this notification are suitable as carriers of lipophilic substances, e.g. fat-soluble biological agents, therapeutics and poisons, etc. and also have a high practical value for their use in relation to amphiphilic water-soluble substances, especially when their molar mass is greater than 1000.

The transferases can also contribute to the stabilization of hydrolysis-sensitive substances and allow for improved distribution of agents in the sample and at the site of application, as well as a more favourable time course of the action of the active substance.

The formulations described are optimized according to the invention for topical application at or near permeability barriers. Application to the skin or the plant cuticle is likely to be of particular interest (but they are also well suited for oral (p.o.) or parenteral (i.v.i.m. or i.p.) application, especially if the transferome compositions are chosen so that losses at the application site are small). Substances or components which are degraded, absorbed or diluted particularly strongly at the application site are ultimately particularly valuable depending on the purpose of application.

In the medical field, up to 50, often up to 10, and especially less than 2.5 or even less than 1 mg of the carrier substance per cm2 of skin are preferred; the optimal amount depends on the carrier composition, intended intensity and duration of action, and the site of application.

In particular, the total amphiphilic substance content for application to human and animal skin shall be between 0,01 and 40% by weight of the transferred serum, preferably between 0,1% and 15% by weight and, preferably, between 1% and 10% by weight.

For plant application, the total amphiphilic content shall be between 0,000001 and 10 weight per cent, preferably between 0,001 and 1 weight per cent and preferably between 0,01 and 0,1 weight per cent.

Depending on the intended use, the formulations of the invention may also be suitable solvents up to a concentration determined by the respective physical (no solubilization or significant shift to optimal), chemical (no impairment of stability), or biological or physiological (minor undesirable side effects) tolerability.

Preferably, unsubstituted or substituted, e.g. halogenated, aliphatic, cycloaliphatic, aromatic or aromatic-aliphatic hydrocarbons, e.g. benzene, toluene, methylene chloride or chloroform, alcohols, e.g. methanol or ethanol, butanol, propanol, pentanol, hexanol or heptanol, propandiol, erithritol, low-carbon esters, e.g. acetic acid alkyl esters, ethers such as diethyl ether, dioxan or tetrahydrofuran, or mixtures thereof, are considered.

The lipids and phospholipids which are suitable for use within the meaning of this application, in addition to those mentioned above, are described in Form and Function of Phospholipids (Ansell & Hawthorne & Dawson, authors), Gunstone's Introduction to the Chemistry and Biochemistry of Fatty Acids and Their Glycerides and other reference works. The lipids and surfactants and other relevant active substances are known and their manufacture. An overview of the commercial polar lipids and the brands under which they are marketed by the manufacturers is given in the yearbook McCheon's, Emulsifiers & Detergents, Cutting Manufacturing Co., Publishing Co., Confectionery.A current list of pharmaceutically acceptable active substances is available, for example, in the German Pharmacopoeia (and the respective annual edition of the Red List), and in the British Pharmaceutical Codex, European Pharmacopoeia, Farmacopoeia Ufficiale della Repubblica Italiana, Japanese Pharmacopoeia, Nederlandse Pharmacopoeia, Pharmacopoeia Helvetica, Pharmacopoeie Francaise, The United States Pharmacopoeia, The United States NF, etc. A detailed list of the enzymes suitable for the invention is contained in the volume Enzymes, 3rd Edition (M. Dixon un E.C. Webb, Academic, San Diego, 1979), where recent developments in the series 'Methinology' are presented.The main agrotechnically interesting substances are listed in the 'The Pesticide Manual' (C.R. Worthing, S.B. Walker, Eds. British Crop Protection Council, Worcestershire, England, 1986, e.g. 8th edition) and in 'Active substances in plant protection and fungal control', published by the Agrar Industry Association (Frankfurt); available antibodies are listed in the 'Linscott's Directory', the main neuropeptides in 'Brain Peptides' (D.T. Krieger, M.J. Brownstein, J.B. Martin, John W. Biley, New York, 1987) and other supplementary publications.

Production techniques for liposomes, which are also predominantly suitable for the production of transferases, are described in Liposome Technology (Gregoriadis, ed., CRC Press) or in older reference works, e.g. Liposomes in Immunobiology (Tom & Six, eds., Elsevier), Liposomes in Biological Systems (Gregoriadis & Allison, eds., Willey), Targeting of Drugs (Gregoriadis & Senior & Trouet, Plenum), etc., as well as in the relevant patent literature.

The stability and permeability of transferases can be determined by filtration, possibly under pressure, by a fine-porous filter or by other controlled mechanical agitation, shearing or shredding.

The following examples illustrate the invention without limiting them: temperatures are given in degrees Celsius, carrier sizes in nanometers, pressures in pascals and other quantities in common SI units.

Ratio and percentage are molar unless otherwise stated.

Examples 1 to 4 The following summary:

0 - 500 mg
0 - 500 mg
4.50 ml	Puffer, pH 7,3

Manufacture:

After removal of the solvent in the rotary evaporator, a thin film of solvent remains on the plunger. This film is further dried in a vacuum (below 10 Pa) and then hydrated by a very large lipid spray and therefore suspended by mechanical tubing. The liquid is usually obtained in a dynamic suspension, which is always illuminated by a microscope. The resulting suspension is also designed to produce a dynamic light.

The liposomes for the comparison tests are produced by an analogue process from pure phosphatidylcholine.

Determination of the carrier permeability:

A carrier suspension is driven through the constrictions in an artificial permeation barrier at a given external pressure. The amount of material coming through the constriction per unit time is determined by volumetric or gravimetric methods. From the total area (commission area of the material), the (drive) pressure, time and the amount of penetration, the permeation capacity (P) of the suspension in the system under test is calculated as follows: $\text{P =}\frac{\text{Penetratmenge}}{\text{Zeit x Fläche x Antriebsdruck}}$

The measurement is repeated independently for several pressures. The relative dependence of the permeability, which is a measure of the deformability of the carrier, is calculated from the results of such measurements, depending on the mechanical stress or pressure.

The permeation capability for such series is measured at 62°C to ensure that both lipids are present as a fluid phase.

The results of such a series of measurements for examples 1 to 4 are shown in Table 1. Table 1 shows that the permeability increases sharply, not linearly, with increasing drive pressure and is several orders of magnitude higher at high droplet loads (0.7 MPa) than at low loads (0.3 MPa). However, such a pronounced non-linear relationship applies exclusively (in the sense of a differentiation criterion) to transferomas and not to liposomes. Other Tabelle 1

Proben-Endgröße beschreibung	Druck	Permeations-fähigkeit	Ausgangsgröße
	(MPa)		(nm)	(nm)
SPC/DSPE - PEG	0,7	21,3	225,7	92,6
70/30 mol%	0,6	18,7		94,5
10% Lipidlsg.	0,5	10,9		96,1
rehydratisierte	0,4	2,8		96,1
Probe	0,3	0,007		100,5
SPC/DSPE - PEG	0,7	12,2	217,3	96,3
60/40 mol%	0,6	13,2		100,7
10% Lipidlsg.	0,5	12,2		120
rehydratisierte	0,4	3,39		99,1
Probe		0,3	0,002	wenig Filtrat

Examples 5 - 6 The composition:

410,05 mg, 809,25 mg Bohnen
289,95 mg, 190,75 mg
7 ml, 10 ml	Puffer, pH 7,3

Manufacture:

The lipid content is selected so that the final formula contains both lipid components in a molar ratio of 1/1 and 3/1 respectively. The corresponding amounts of phosphorlipid are weighed in a 50 ml round flask and dissolved 1:1 in 1 ml of chloroform/methanol. After removal of the solvent in the rotary evaporator, a suspension is obtained from the film with a medium radius of approximately 450 nm, as described in examples 1 to 4.

Determination of carrier permeability

The determination of carrier permeability is carried out according to the procedure described in examples 1-4 and the corresponding results are shown in Figure 4. They show that the addition of didekanoylphosphatidylcholine significantly increases the carrier permeability, depending on the concentration, especially at high pressure. Carriers formed from SPC and didekanoylphosphatidylcholine in a molar ratio of 1/1 (excluding those with a molar ratio of 3/1) have a significantly higher permeability than liposomes formed from pure SPC.

The values of the permeability for the measured media in examples 5 to 6 are summarised in Table 2.

The 10% suspension containing pure didecanoylphosphatidylcholine is milky cloudy. This suspension contains carriers with a mean diameter of 700 ± 150 nm and forms a soil set. This behaviour clearly shows that the lipid is not soluble either per se or in combination with SPC in the relevant concentration range. Other Tabelle 2

Probenbeschreibung	Porendurchmesser (nm)	Druck (MPa)	Permeationsfähigkeit
Probe: 3 : 1	50	0,9	0,00039
	100	0,5	0,0083
		0,6	0,021
		0,7	0,04
		0,8	0,05
		0,9	0,066
Probe: 1 : 1	50	0,9	0,16
	100	0,5	0,052
			0,021
		0,6	0,12
			0,17
		0,7	0,27
			0,22
		0,8	0,76
			0,69
		0,9	0,66
			0,60

Example 7

345,6 mg
154,4 mg
4,5 ml	Puffer, pH 7,3

A suspension of SPC/DSPE-maltobionamide is prepared in the molar ratio 3:1 according to the method described in examples 5-6. The resulting media have an exceptionally good permeability. The size of the media is determined before and after each measurement to determine the permeability. The measurements are used to demonstrate that no solubilization of the media occurs at any time.

The permeability of the media is determined at a pressure of 0.4 MPa and, unlike in examples 5 and 6, at a temperature of 52 °C. At this pressure, the permeability of the media observed by the artificial permeability barrier is good enough. The lipid (glyco-lipid) added is not capable of solubilising the phospholipid. An examination of the suspension by dynamic light scattering and optical microscopy does not indicate the existence of a solubilised (miscellular) phase. The final size of the particle after permeation by the artificial permeability barrier is between 81 and 98 nm, depending on the drive pressure (0.3-0.9 MPa; with a tendency to fall)

Pure glycolipid does not dissolve or form a miscellaneous suspension, but forms a vesicle suspension. To prove this, an experiment was undertaken to demonstrate the osmotic activity of DSPE in an aqueous medium. For this purpose, the lipid suspension was diluted with water. Due to the resulting concentration difference, water enters the vesicles.

Examples 8 - 17 The composition:

203 - 86,5 µl
9.04 - 61.4 mg
1 ml	Phosphatpuffer (nominal: pH 6,5)

The carriers are produced as SPC/Diclofenac mixtures in a molar ratio of 4:1 to 1:4 as described in Examples 1-4.

The resulting solutions are not clear (Figure 5), but show opal precipitation. On the other hand, the mixtures 4:1, 3:1 and 2:1 show a significant precipitation. After 5 minutes of standing, the other suspensions also cloudy, with the mixtures 1:2, 1:3 and 1:4 showing a flaky precipitation (Table 3).

Determination of the carrier permeability:

The carrier permeability, which is a measure of carrier deformability, is determined as described in the previous examples, and the following permeability values (P) are obtained for the mixtures of 15 mg/ml, 20 mg/ml and 25 mg/ml diclofenac at a pressure of 0,3 MPa (driving pressure): 6x10-11 m/Pa/s, 10-10 m/Pa/s and 2,5x10-10 m/Pa/s.

These values are comparable to those of known transferases measured under similar conditions (SPC/NaChol 3/1 M/M; 2 W/%: 3x10-10 m/Pa/s), which shows that SPC/Diclofenac mixtures of appropriate composition have a very high permeability and must therefore be extremely deformable, although they are not soluble at any time or concentration point. Other TABELLE 3

Mit HCl wird der pH auf 7 - 7,2 pH eingestellt und 2 min beschallt.
Nach Beschallen:	1:1.0	leicht trüb
	1:1.2	trüb, flüssig, Kristalle in Lsg. ca. 20 pro Sicht-feld
	1:1.4	trüb, flüssig, Kristalle in Lsg. ca. 20 pro Sicht-feld
	1:1.6	trüb, flüssig, Kristalle etwas größer
	1:1.8	trüb, zähflüssig, Zusammenballung von Kristallen
	1:2.0	trüb, zähflüssig, sehr viele Kristalle
	1:2.2	trüb, zähflüssig, sehr viele, sehr große Kristalle

Examples 18 to 25: The composition:

475 - 325 mg
25 - 175 mg
5 ml	Puffer, pH 6.5

Manufacture:

The preparation is as described in examples 1 to 4, except that after suspension of the mixture the pH is adjusted to pH 7 by adding 10 M NaOH, producing 5 ml ibuprofen-containing transfer salts with increasing ibuprofen and decreasing SPC (in 25 mg steps) each, with a total lipid concentration of 10%.

Microscopic inspection of the resulting suspensions:

Sample 1: no crystals, very large carriers; sample 2: no crystals, very large carriers; sample 3: only blinking in the background; sample 4: very few small crystals; sample 5: no crystals, droplets; sample 6: mostly crystals; sample 7: droplets, few very large crystals.

Determination of the carrier permeability:

The determination of carrier permeability is carried out as described in the previous examples. The results of this measurement are shown in Figures 6 and 7. The phospholipid-active mixture tested shows a typical transferase behavior throughout, especially in the concentration range of 35 mg/ml and above. The carrier ibuprofen concentration does not cause solubilization.

Comparison examples A - E The Commission has also been asked to provide a detailed description of the measures taken. The composition:

120 mg	Dipalmitoylphosphatidylcholin (DPPC)
24 mg	Ölsäure
20 mg	Arginin
60 ml	PBS (eine Tablette in 200 ml dest. Wasser auflösen)

120.0 mg DPPC and 24.1 mg oleic acid were weighed in a 100 ml glass. The two reagents were then mixed. A phosphate buffer salt (PBS) tablet was dissolved in 200 ml of water. The water was completely dissolved to form a 10 mM (PBS) buffer. 20 mg arginine was then dissolved in 60 ml PBS, pH 7.46, and added to the lipid mixture. The resulting solution was heated to 40-45°C for half an hour and homogeneously

Comparison example B (Example 9 from EP-A 0 280 492)

270 mg	Dipalmitoylphosphatidylcholin (DPPC)
30 mg	DSPC
60 mg	1-Octadecansulfonsäure (ODS)

270.05 mg (DPPC), 30.1 mg DSPC and 60.01 mg 1-octadecansulfonic acid (ODS) were dissolved in chloroform/methanol 1:1. The sample was compressed to dry in a rotary evaporator for two hours. The sample was then vacuum-dried for another hour. The residue was rehydrated with 10 ml PBS. The mixture was heated to 60°C and homogenised. The sample was then exposed to an ultrasonic source for 5 minutes.

The Commission considers that the aid measure is compatible with the internal market. The composition:

400 mg	Setacin F spezial-Paste (Disodiumlaurylsulfo- succinat)
580 mg	hydrogeniertes PC (PHPC)
200 mg	Minoxidil Acetatpuffer pH 5,5

400 mg Setacin F special paste, 580.03 mg PHPC and 200.03 mg minoxidil were weighed in a glass and dissolved in chloroform/ methanol 1:1 and transferred to a round flask. The lipid mixture was compressed in a rotary evaporator for approximately 2.5 hours and then dried completely in a vacuum. The sample was then swirled in a warm bath at 50°C and rehydrated with 10 ml of acetate buffer.

1 mg deferoxamine mesylate was added as an antioxidant, and the pH of the solution was adjusted to approximately 7.24 by adding 1 drop of 10 mM HCl, and the solution was made macroscopically homogenous at 35°C in water under stirring.

Comparison example D (Example 4 from EP-A 0 220 797) The composition:

400 mg	gereinigtes hydriertes Sojabohnen-Lecithin
40 mg	HCO-60 (Polyoxyethylen hydriertes Rhizinusöl)
100 mg	Vitamin E
9,46 ml	bidest. Wasser

400.04 mg Phospholipon 90 H (hydrated soybean lecithin), 40 mg Eumulgin HRE 60 (polyoxyethylene hydrated castor oil) and 100.11 mg Vitamin E were weighed in a 100 ml glass and filled with 9.46 ml of bidest. Water was added. The sample was stirred for 45 minutes until almost all was dissolved. The lipid solution was then resuscitated in the ultrasonic bath at 79°C for 10 minutes. To complete the solution, the sample was resuscitated and resuscitated for 10 minutes in the ultrasonic bath at 56°C.

The Commission has also been asked to provide a detailed description of the measures taken. The composition:

300 mg	SPC
150 mg	Octadecyltrimethylammoniumbromid
2550 µl	dest. Wasser

300 mg SPC and 150 mg Octadecyltrimethylammonium bromide were weighed in a 100 ml glass and dissolved 1:1 with 1 ml chloroform/ methanol.

The sample was compressed in vacuum until dry, water was added to produce a 1% solution and the resulting solution was stirred for 15 minutes.

The sample preparations of the comparison samples A to E were carried out in accordance with the relevant provisions of the aforementioned printed documents (unless otherwise stated).

Figure 8 shows the permeability (at a constant pressure of 0.9 MPa) of the comparator examples A-E and of an ibuprofen/SPC transferome of the invention in the form of a bar graph.

Claims (33)

1. The use of liquid droplets suspensible in a liquid medium and coated with a membrane-like coating composed of one or several layers of an amphiphilic carrier substance, wherein the carrier substance comprises of at least two (physico)-chemically different components that differ in solubility in the suspension medium of the preparation, usually water, by a factor of at least 10 and wherein the content of solubilizing components is less than 0.1 mol % relative to the content of these substances, whereby the point of solubilization of the coated droplets is reached, or else this point of solubilization cannot be reached, for the manufacture of a preparation for the non-invasive application or for the non-invasive transport of at least one active agent, in particular for medicinal or biological purposes, into and through barriers and constrictions such as are presented by the skin and similar structures.
2. The use according to claim 1, characterized in that the amphiphilic components are selected such that independent of concentration no solubilization occurs.
3. The use according to any one of claims 1 and 2, characterized in that the solubility, in particular the solubility in water of the soluble component(s) is at least 10^-3 and up to 10^-6 M, and the solubility, in particular the solubility in water, of the less soluble component(s) is at least 10^-6 and up to 10^-10 M.
4. The use according to any one of claims 1 to 3, characterized in that the difference in solubility of the soluble component(s) and the less soluble component(s) is approximately from 10 to 10⁷, preferably from 10² to 10⁶ and particularly preferably from 10³ to 10⁵.
5. The use according any one of claims 1 to 4, characterized in that the capability of the preparation to permeate constricted passages, amounts to at least 0.01 per thousand, preferably 1 per thousand, of the permeability of small, essentially unhindered permeating molecules.
6. The use according any one of claims 1 to 5, characterized in that the ratio of the permeation capacity versus the reference particles P_(Transf.)/P_(Refer), wherein the reference particles, for example water, are much smaller that the constrictions in the barrier, if the barrier itself is the site of measurement, is from 10^-5 to 1, preferably from 10^-4 to 1 and particularly preferably from 10^-2 to 1.
7. The use according any one of claims 1 to 6, characterized in that the preparation comprises at least two amphiphilic components of differing solubility for the formation of a carrier substance and/or a membrane-like coating of a droplet amount of hydrophilic liquid, wherein the active agent is contained in the carrier substance, in or on the membrane-like coating and/or in the hydrophilic liquid.
8. The use according any one of claims 1 to 7, characterized in that the vesicle radius of the coated droplets is from approximately 25 and to 500 nm, preferably from approximately 50 to approximately 200 nm, particularly preferably from approximately 80 to approximately 180 nm.
9. The use according any one of claims 1 to 8, characterized in that the coating forms a double layer.
10. The use according any one of claims 1 to 9, characterized in that the amphiphilic component(s) comprises physiologically acceptable lipids of differing polarity and/or such an active agent or active agents, respectively.
11. The use according any one of claims 1 to 10, characterized in that the amphiphilic substance comprises a lipid or lipoid of biological origin or a corresponding synthetic lipid or a derivative of such lipids, in particular a diacyl- or dialkyl-glycerophospho-ethanolamine azopolyethoxylene derivative, didecanoylphosphatidylcholine, diacylphospho-oligomaltobioamide, a glyceride, glycerophospholipid, isoprenoid lipid, sphingolipid, steroid, sterin or sterol, a sulphur- or carbohydrate-containing lipid, or another lipid that forms stable structures, for example double layers, preferably a half-protonated liquid fatty acid, in particular a phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, a phosphatidic acid, a phosphatidylserine, a sphingomyelin or sphingophospholipid, glycosphingolipid (for example cerebroside, ceramidepolyhexoside, sulfatide, sphingoplasmalogen), ganglioside or other glycolipid, or consists of a synthetic lipid, preferably a dioleoyl-, dilinolyl-, dilinolenyl, dilinoloyl-, dilinolinayl-, diarachinoyl-, dilauroyl-, dimyristoyl-, dilalmitoyl-, distearoylphospholipid or a corresponding dialkyl- or sphingosine derivative, glycolipid and other equal or mixed chain acyl- or alkyl-lipids, respectively.
12. The use according any one of claims 1 to 11, characterized in that the less soluble amphiphilic component comprises a synthetic lipid, preferably myristoleoyl-, palmitoleoyl-, petroselinyl-, petroselaidyl-, oleoyl-, elaidyl-, cis- or trans-vaccenoyl-, linolyl-, linolenyl-, linolaidyl-, octadecatetraenoyl-, gondoyl-, eicosaenoyl-, eidosadienoyl-, docosatetraenoyl, caproyl-, lauroyl-, tridecanoyl-, myristoyl-, pendadecanoyl-, palmitoyl-, heptadecanoyl-, stearoyl- or nonadecanoyl-glycerophospholipid or a corresponding branched chain derivative or a corresponding sphingosine derivative, glycolipid or other acyl- or alkyl-lipids; and the more soluble amphiphilic component(s) is/are derived from one of the above less soluble components and a derivative is formed by the use of butanoyl-, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, dodecan or undecanoyl or one of the appropriate singly or several times unsaturated or branched-chain substitutes thereof or several substitutes independent of each other and/or substituted, complexed and/or associated with another appropriate solubility-enhancing material.
13. The use according to any one of claims 1 to 12, characterized in that the total content of amphiphilic substances for application on human and animal skin amounts to from 0.01 to 40% by weight, preferably from 0.1 to 15% w/w and particularly preferably from 1 to 10% w/w.
14. The use according to any one of claims 1 to 13, characterized in that the total amount of amphiphilic substance for application to plants is from 0.000001 to 1% w/w, preferably between 0.001 and 1% w/w and particularly preferably between 0.01 and 0.1% w/w.
15. The use according any one of claims 1 to 14, characterized in that it contains, as the active substance, an agent that is adrenocorticostatic, an androgen or antiandrogen, antiparasitic, anabolic, anaesthetic or analgesic, antiallergenic, antiarrhythmic, antiarteriosclerotic, antiasthmatic, and/or bronchospasmolytic, antibiotic, antidepressant and/or antipsychotic, antidiabetic, antidote, antiemetic, antiepileptic, antifibrinolytic, anticonvulsive, anticholinergic, an enzyme, coenzyme or corresponding inhibitor, an antihistamine, antihypertonic, a biological activity inhibitor, antihypotonic, anticoagulant, antimycotic, antimyasthenic, an agent to treat Parkinson or Alzheimer disease, antiphlogistic, antipyretic, antirheumatic, antiseptic, respiratory analeptic or stimulant, broncholytic, cardiotonic, chemotherapeutic, a coronary dilatator, cytostatic, diuretic, a ganglion blocker, a glucocorticoid, antiinfluenza, haemostatic, hypnotic, an immunoglobulin or fragment or another immunological or receptor substance, a bioactive carbohydrate (derivative), a contraceptive, antimigraine, a mineralcorticoid, a morphine antagonist, muscle relaxant, narcotic, neuro- or CNS-therapy, nucleotide or polynucleotide, neuroleptic, neurotransmitter or corresponding antagonist, a peptide (derivative), an ophthalmologic, (para)-sympathomimetic, a protein (derivative), a psoriasis/neurodermatitis agent, a mydriatic, psychostimulant, rhinologic agent, sleep inducing agent or its antagonist, a sedative, spasmolytic, tuberlostatic, urologic, a vasonconstrictor or -dilator, a virostatic, or a wound-healing agent or several such agents, in particular diclofenac or ibuprofen.
16. The use according to one of claims 1 to 15, characterized in that the agent is a non-steroidal anti-inflammatory, for example diclofenac, ibuprofen or a lithium-, sodium-, potassium-, caesium-, rubidium-, ammonium-, monomethyl-, dimethyl-, or trimethylammonium or ethylammonium salt thereof.
17. The use according to one of claims 1 to 16, characterized in that the less polar component comprises a physiologically tolerated lipid, preferably in the class of phospholipids and particularly preferably in the class of phosphatidylcholines, and that the active agent is, where appropriate with an addition of less than 10% w/w relative to the total composition of the preparation, the soluble component, wherein the concentration of the soluble component(s) is typically from 0.01% w/w to 15% w/w, preferably from 0.1% w/w to 10% w/w and particularly preferably from 0.5% w/w to 3% w/w and the total lipid concentration is from 0.005% w/w to 40% w/w, preferably from 0.5% w/w to 15% w/w and particularly preferably from 1% w/w to 10% w/w.
18. The use according to any one of claims 1 to 17, characterized in that the preparation contains consistency builders such as hydrogels, antioxidants such as probucol, tocopherol, BHT, ascorbic acid, desferroxamine and/or stabilizers such as phenol, cresol, benzyl alcohol or similar substances.
19. The use according to any one of claims 1 to 18, characterized in that the active substance is a growth modulating substance for living organisms.
20. The use according to any one of claims 1 to 18, characterized in that the active substance has biocidal properties, in particular insecticidal, pesticidal, herbicidal or fungicidal.
21. The use according to any one of claims 1 to 28, characterized in that the active substance is an attractant, particularly a pheromone.
22. A method of manufacture of a preparation for use in accordance with any one of claims 1 to 21, characterized in that at least two amphiphilic components are selected that differ by a factor of at least 10 in their solubility in the suspension medium of the preparation, usually water, and that the content of solubilizing components is less than 0.1mol % relative to the content of these substances, at which the solubilization point of the coated droplets is reached, or else this point cannot be reached in practice in the relevant range, and the amount of the amphiphilic components is set in such a way that the capability of the preparation to permeate through constrictions, amounts to at least 0.01 thousandth of the permeation capacity of water.
23. A method according to claim 22, characterized in that the amount of amphiphilic components is adjusted such that the ratio of the permeation capacity versus that of water, when the barrier itself is the site of measurement, lies from 10^-5 to 1, preferably from 10^-4 to 1, particularly preferably from 10^-2 to 1.
24. A method according to any one of claims 22 and 23, characterized in that the stability and permeation capacity are determined by means of filtration, if appropriate under pressure, through a fine-pore filter or through otherwise controlled mechanical fluidization, shearing or fragmentation.
25. A method according to any one of claims 22 to 24, characterized in that the mixture of substances, for the production of a transfersome®-type of preparation, undergoes filtration, ultrasound, stirring, shaking or other mechanical form of fragmentation.
26. A method according to any one of claims 22 to 25, characterized in that transfersome®-type droplets forming the preparation are produced from at least two amphiphilic components of differing polarity, at least one polar liquid and at least one active substance.
27. A method according to any one of claims 22 to 26, characterized in that transfersome®-type droplets forming the preparation are produced from at least two amphiphilic components of differing polarity and at least one polar liquid , wherein the amphiphilic component(s) comprises or includes the active substance.
28. A method according to any one of claims 22 to 27, characterized in that the amphiphilic components and the hydrophilic substance with the active substance are separately mixed and, where appropriate, placed in solution, the mixtures or solutions then being mixed together and with the addition of particularly mechanical energy the droplets are formed.
29. A method according to any one of claims 22 to 28, characterized in that the amphiphilic components are added to a polar solution either as such or dissolved in a physiologically acceptable solvent or solubilizer miscible with polar liquid(s), particularly water.
30. A method according to any one of claims 22 to 29, characterized in that the formation of the coated droplets is achieved by stirring and evaporation out of a reverse phase, using an injection or dialysis procedure, using electrical, thermal of mechanical means such as shaking, stirring, homogenizing, ultrasound, trituration, freezing, or thawing, heating or cooling or high- or low-pressure filtration.
31. A method according to any one of claims 22 to 30, characterized in that the formation of coated droplets is achieved by filtration and the filter material has a pore size of 0.01 to 0.8 µm, preferably 0.05 to 0.3 µm and particularly preferably 0.08 to 0.15 µm, wherein, if appropriate, a series of several successive filters can be employed.
32. A method according to any one of claims 22 to 31, characterized in that the carrier-active agent combination occurs at least partially after formation of the droplets.
33. A method according to any one of claims 22 to 32, characterized in that the coated droplets are prepared from a concentrate or lyophilisate shortly before their use.