DE19522693A1 - Composition for the production of finely dispersed systems and process for their production - Google Patents

Abstract

A composition contains at least one phospholipid, at least one bile acid and/or at least one bile acid derivative, ethanol and water. This composition is useful for preparing finely dispersed systems that remain stable even after a long storage time. The finely dispersed systems are particularly useful for preparing pharmaceutical or cosmetic compositions and have biological activity although they do not contain a usual pharmaceutical active substance.

Description

The present invention relates to a new composition, which is particularly suitable for the production of finely dispersed Sy steme, and a process for their preparation and their Ver turn.

The prior art contains numerous publications that prove that the effectiveness of amphiphilic and lipophilic active pharmaceutical ingredients can be increased can (i.e. better bioavailability is achieved, a ge lower dosage is required and a lower one Toxicity is the consequence) if such active substances are in finely dispersed vesicular or particulate systems can be incorporated. Despite To date, there are only a few remedies on the ba sis finely dispersed galenics on the market. The reason for this may be On the one hand, it can be seen that the development of a sol product, among other things due to official requirements, takes many years, on the other hand they are so far knew preparations not stable over the long term, which makes them suitable for Marketing is out of the question.

The intrinsic functionality, i. H. the biological effect of fine disperse systems without containing an active ingredient So far no importance has been attached and therefore it has been not examined.

No compositions are known from the prior art, who manufacture finely dispersed, liquid systems with a Long-term stability required for marketing possible chen. Liquid systems are those with a viscose understood from 0.9 to 100 mPa · s.

The present invention therefore has the technical problem based on specifying a composition that the manufacture long-term stable finely dispersed systems enabled, the Zu composition have their own functionality at the same time,  d. H. have cosmetic or therapeutic properties should, without further conventional pharmaceutical or cos active ingredients are included.

According to the invention, this problem was solved by a combination setting, comprising the following components:

• a) at least one phospholipid,
• b) at least one bile acid and / or at least one of them Derivatives,
• c) ethanol and
• d) water.

From the composition mentioned can be easily with commercially available devices nanodisperse lipid / water formulation manufacture stanchions, preferably nanoemulsions, nanocolloids and Liposomes that are stable for a long time when stored and a own functional effectiveness in vivo and in vitro, in particular those in the cosmetic and pharmaceutical sector sen. The composition can be easily with different active ingredients fen be loaded, the composition of the active ingredients gives increased stability and effectiveness.

The phospholipid of the composition is preferably a Phos phatidylcholine of pharmaceutical quality, the aliphati residues of the phospholipid, preferably 12-22 carbon atoms with up to to include 4 cis double bonds, with unbranched aliphati cal residues are particularly preferred. A is particularly preferred Phospholipid, in which the aliphatic radicals have 16-20 carbon atoms and include a maximum of 3 cis double bonds, as in natural ones vegetable lecithins, e.g. B. soybean lecithin, the ali phatic radicals R₁ and R₂ an equal or unequal number of Can have carbon atoms. The phospholipid can also naturally be of semi-synthetic or fully synthetic origin.

The bile acid and / or its derivatives can also be natural be of semi-synthetic or fully synthetic origin. Preferred  Derivatives are salts of bile acid, for example sodium salt ze.

Cholic acid and deoxychol are particularly preferred as bile acid acid, glycolic acid, taurocholic acid, taurodeoxycholic acid, ur socholic acid, chenoxycholic acid. Preferred derivatives are sodium cholate, sodium deoxycholate, sodium glycocholate, sodium tauro cholate, sodium taurodeoxycholate, sodium urocholate and sodium chenoxycholate.

As ethanol, preferably 96% ethanol according to DAB 10 is used turns. Ethanol appears to achieve long-term stability of finely dispersed systems over a period of more than 18 months to be essential.

In comparative experiments, ethanol-free preparations have shown that otherwise correspond to the composition according to the invention, as proven physically unstable. Freshly made ethanol free preparations were also ineffective in vivo.

The composition of the invention is preferred as a con provided in which the phospholipid in a Concentration from 5 to 250 mg / ml, preferably 40 to 200 mg / ml is contained and the bile acid and / or its (e) derivative (s) in a molar ratio of 2 to 10 to 1 (lipid to cholate) is (are) included. Ethanol is preferred in one ratio of 1: 1 to the phospholipid (V / G) included.

Use the ethanol in a ratio of 1: 1 Detect phospholipid (volume ethanol / weight phospholipid) ver lends the composition a special stability and ease also supports the manufacturing process of the finely dispersed system me, and furthermore this ethanol content is for the intent effectiveness is particularly advantageous.

The concentrate according to the invention is for use in a ver Ratio of 1: 1 to 1: 200, preferably 1: 1 to 1:40 and particularly preferably diluted 1: 5 to 1:20. Serve as a diluent  thereby water or salt solutions, preferably those with 0.1 to 0.9 % By weight of table salt.

Particularly stable systems are achieved with one set tongue, the 100 g phospholipid, 0.2 g tocopherol, 100 ml 96% Ent and 13.4 g of sodium cholate per liter of aqueous solution holds.

The composition preferably comes as a finely dispersed system based on lipid mixtures, micelles, mixed micelles, um sweeping micelles, uni-, oligo- or multilamellar liposomes, Nanoemulsions, nanoparticles or nanocolloids are used. "Finely dispersed systems" are systems with particles understood, the diameter of which is approximately 4 to 500 nm. Of the Diameter of the particles is preferably less than 250 nm, very particularly preferably less than 100 nm. The best is below addiction are the vesicular systems.

The composition preferably contains a pharmaceutical and / or cosmetic adjuvant, with long-term stability of finely dispersed systems over several years, however, without these auxiliaries can be achieved. To the stability of the Collaborative expansion of finely dispersed systems can composition z. B. antioxidants are added, if as Phos an unsaturated phosphatidylcholine is used. In tocopherol is usually added as an antioxidant. From medical African aspects, such as achieving the Isotonicity and for reasons of osmolarity, salts, in particular table salt or buffer substances are added, as described for example in EP-A-0056781, DE-A-40 26 833, DE-A-40 26 834, EP-A-0475160, EP-A-0613685 and W094 / 01089. As Excipients, such as those commonly used in pharmaceuticals and / or Cosmetics used are, in addition to antioxidants, salts and buffers Cotenside such. B. polysorbate or free Fatty acids, thickeners and also preservatives prefers.  

The composition is particularly suitable for the manufacturer a pharmaceutical preparation. As stated above the composition as such has biological activity, which they use as special in the therapeutic field makes it seem useful.

The inherent properties of the drug-free composition make these particularly suitable for the treatment of bacteria len and viral infections (as well as AIDS), for the treatment of Cancer, Alzheimer's disease, Crohn's disease and ulcerative colitis, asthma, Bronchitis, high blood pressure and also hypoxia. Still is the pharmaceutical preparation according to the invention effectively turned on has been used for the treatment of skin diseases and Be act of dry eye and dry mouth. In the Topical application on the skin and on the eyelids was shown that non-oily formulations for the therapy of all skin gien and significantly effective for the therapy of the dry eye were. The optional addition of vitamin C continued to show ne antiviral and anticancerogenic effectiveness.

One of the effects of the finely dispersed system is likely attributable to the fact that with in vivo application (oral or systemic, e.g. B. i.m., i.v.) existing noxa "thinned out" who den: By supplying membranes that are artificially produced represents, but consist of natural phospholipids and therefore are non-toxic and fully metabolizable, in form finely dispersed systems, the total membrane surface in Kör perfluids increased. The ability of these membranes in vivo Toxins, histamine, metabolites, pollutants, even oxygen to bind and to quickly remove them renally or biliary from the body distant, relieves the blood cells and leads to a passive, purely physicochemical detoxification and thus to a reduc tion of the noxae.

The intrinsic functionality of the systems can be determined by connecting and / or Storage of active substances / substances in a synergistic manner reinforce. The increase in effectiveness through the combination of finely dispersed system and the active ingredient is probably on it  attributed that the finely dispersed system the active ingredient in vi vo particularly finely dispersed in cell membranes and thus its Effectiveness increased.

In a preferred embodiment, the inventive Pharmaceutical preparation vitamin C or one of its deri vate. Vitamin C is usually in a concentration from 0.0002 to 120 mg / ml.

This concentration range is so large because it is complete different application routes are possible, for example topically on the skin (occlusive, but only sprayed on), oral, IV, IM, intralymphatic and inhalation, and as Test kit in vitro. Based on vesicular systems with 10% Phos pholipid, the concentration of vitamin C is preferably between 1 and 100 mg / ml.

In a further embodiment of a phar according to the invention pharmaceutical preparation, the composition is in gelatin, for example hard or soft gelatin capsules.

It has surprisingly been found that the finely dispersed Sy stem, especially in the form of liposomes, the ATP level in can lower several experimental cell culture systems. Next surprisingly, it was found that the composition can lower the cAMP level of isolated rat cortex. This Surprising findings enable the use of the invention moderate composition for the prophylaxis and / or therapy of Diseases where it is desirable to use the ATP and / or lower cAMP levels. These diseases include, for example Cancer and Alzheimer's disease. Together With cancer, it has been found that cancer cells have a have increased cAMP levels and that the lowering of the cAMP level can eliminate the malignant phenotype. Furthermore was found in Alzheimer's disease that the lowering of the ATP level leads to relief of the symptoms of the disease.  

The preparation according to the invention furthermore shows to be finely dispersed ses system, especially in the form of liposomes, in a lympho cytocyte culture an increased oxygen consumption and a signifi edge temperature increase. Furthermore, it was found that it was too in vitro formation of oxygen radicals (formation of oxonium ions) comes, the release of such radicals by the addition is additionally strengthened by vitamin C.

By adding or storing known active ingredients (e.g. against pain or high blood pressure) their effect can be amplify synergistically, and it also escape anti-ignition properties.

This property of the preparation according to the invention also allows their use as an immunostimulating agent.

In addition, the preparation according to the invention shows a sig significant dose-dependent toxicity on leukemia cells (HUT78, L578Y), which could be increased synergistically by vitamin C. When testing with peripheral lymphocytes, the toxicity of the increase increased composition significantly. This opens the way Prophylaxis and / or Thera composition according to the invention pie of cancer diseases (see also example 6) and the pro phylaxis and / or therapy of monoclonal, polyclonal or malignant gammopathies, primary, secondary or combined Immunodeficiency diseases, autoimmune polyendocrinopathies and Au use toimmune diseases. With autoimmune diseases it can be organ-specific, for example perni anemia, chronic gastritis, juvenile diabetes mellitus, as well as non-organ-specific diseases, such as Diseases of the rheumatic type (e.g. rheumatoid Arthritis, scleroderma) or mixed or transitional forms, such as e.g. B. autoimmune haematolytic anemia, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis, Sjögren- Syndrome and multiple sclerosis.

In addition to this suitability for the production of pharmaceutical accessories The composition according to the invention is also suitable for riding  for the production of cosmetic preparations, such Zu Preparations for "simple" skin protection and normal skin care are particularly suitable. Also cosmetic preparations are suitable for incorporation in gelatin.

The composition of the invention can further sub punch, such as dyes, are added. With these together settlements with the particles of the finely dispersed system dyestuffs in particular can be textiles, leather or paper dyed or conditioned.

In a further preferred embodiment, the invented Inventional composition of the usual in kidney dialyzers dialysis liquid used as added. It was observed ensures that the effectiveness of blood purification and detoxifi decoration was increased considerably. The reason for this is likely in the rapid and effective adsorption of amphiphilic Metabo liten to the particles of the finely dispersed system, in particular the liposomes.

The production of finely dispersed systems from the invention Composition can be achieved by adding mechanical energy, such as for example through optimized mixing in static mixers, Pressure filtration, stirring, homogenization or filtration successful Commercially available devices can be used for this, such as for example static mixing systems or homogenizers Gaulin or a microfluidizer. With these ver drive more than 10 mg / ml oil, based on the composition, added, the process leads to nanoemulsions or nano colloids, and without the addition of oils or oil concentrations of  3 mg / ml, based on the composition, leads the process to liposomes.

All such "pharmaceutical" oils can be used as such oils the, such as B. Miglyol, jojoba oil, borage oil, castor oil, Di Stel oil, paraffin oils etc., and also essential oils such as Olbas, Tea tree oil, peppermint oil, etc.  

example 1

10 g soy lecithin (phosphatidylcholine content 97%) are in 10 ml of 96% ethanol dissolved. 650 mg table salt and 1.3 g sodium cho lat are inject in 180 ml of water. solved. Both solutions who the united and sterile filtered at 3.5 bar. The resulting finely dispersed system is made by diluting with isotonic cooking saline solution or just with water to the desired application brought concentration.

Example 2

10 g of soy lecithin as in Example 1 are 96% in 10 ml Ethanol dissolved. 650 mg of table salt and 1.3 g of sodium cholate dissolved in 80 ml of water. Both solutions are combined and in one nem household mixer, e.g. B. SG rod, homogenized. The result The finely dispersed concentrate is diluted with isotoni shear saline or even with water to the desired Application concentration brought.

Example 3

500 g soy lecithin as in Example 1 are 96% in 500 ml Ethanol dissolved. 32.5 g of common salt and 65 g of sodium cholate are in 4 l of water dissolved. Both solutions are combined and in one commercial agitator, e.g. B. Stephan UMC 12, homogenized. The resulting finely dispersed system becomes as in Example 1 by diluting to the desired application concentration brings.

The resulting particles have an average diameter of less than 200 nm (measured with a Coulter light scattering device N4SD). Their diameter changes due to the dilution stopped walking. Dilutions were checked 1: 1, 1: 5, 1:10, 1:20, 1:50, 1: 100, 1: 200, 1: 400.  

Example 4

If an active ingredient is to be stored in the finely dispersed system, there are basically two options, which depend solely on the solubility properties of the active ingredient in question:
Water-soluble active ingredients are dissolved together with the sodium cholate in the aqueous phase before it is combined with the ethanolic lipid solution. Lipophilic active ingredients are dissolved in the ethanol together with the lipid. Oils are dissolved in the ethanolic lipid solution before combining with the aqueous phase or added to the already finished system and stirred with the system a second time.

Of course, such a system can be used simultaneously several different active ingredients can be incorporated.

Are the solubility properties of active ingredients in the finely dispersed system should be stored, bad, so can solubility can be improved by adding co-surfactants, such as B. Polysorbate 80, Arlasolve, free fatty acid such as oleic acid etc., and / or by small additions of other alcohols, such as. B. Isopropanol, glycol or propylene glycol.

If an active ingredient is to be attached to the finely dispersed system, so it becomes in according to its solubility properties additional ethanol or aqueous phase, pre-dissolved, for production given finely dispersed system and incorporated by stirring.

Example 5

Affect active substances in the finely dispersed system in the Basic recipe, such as B. oxidizing agent, can be the desired Storage take place in a two-chamber system, from which the active Substance only shortly before use with the finely dispersed system is mixed.  

Example 6

The patient J.L.S.M, 47 years old, was aged 17 Years diagnosed with a duodenal ulcer. With a routine con trolls in October 1990 also became a prepyloric ulcer detected. Both were more or less controlled. At the routine check in November 1994 showed the endoscopic A biopsy reshaped to a poorly differentiated carcinoma. Thereafter, surgical treatment was recommended and carried out. The patient received 15 days before the operation 30 ml ascorbate-containing liposomes. That ent during the operation removed tissue was examined histologically. Diagnosis: ulcer pepticum with fibrinoid necrosis at the base and regenerative Changes on the edge. No evidence of atypia, no deterioration ture.

Claims (23)

1. Composition comprising the following components:

• a) at least one phospholipid,
• b) at least one bile acid and / or at least one derivative thereof,
• c) ethanol and
• d) water.

2. Composition according to claim 1, characterized in that

• a) the phospholipid has the following general formula: wherein R₁ and R₂ each represent an aliphatic radical having 12 to 22 carbon atoms and having up to 4 cis double bonds, the aliphatic radicals preferably being unbranched.

3. Composition according to claim 1 or 2, characterized net that the bile acid and / or its derivative from cholic acid, Deoxycholic acid, glycolic acid, taurocholic acid, taurodeoxy cholic acid, ursocholic acid and chenoxycholic acid or their salts, preferably the group comprising sodium salts is selected (are). 4. Composition according to one of claims 1 to 3, characterized in that it contains:

• a) the phospholipid in a concentration of 5 to 250 mg / ml, preferably 40-200 mg / ml,
• b) the bile acid and / or its derivative (s) in a molar ratio of 2 to 10 to 1 (lipid to cholate),
• c) ethanol in a ratio of preferably 1: 1 (v / w) to the phospholipid.

5. Composition according to one of claims 1 to 3, characterized ge indicates that by diluting the composition Claim 4 in a ratio of 1: 1 to 1: 200, preferably 1: 1 to 1:40 and particularly preferably 1: 5 to 1:20 is available. 6. Composition according to claim 5, characterized in that the diluent is water or a saline solution is preferred 0.1 to 0.9% saline. 7. The composition according to at least one of claims 1 to 6, characterized in that the composition as finely dispersed system based on lipid mixtures, micelles, mixed media cells, reverse micelles, uni-, oligo- or multilamellar lipo somes, nanoemulsions, nanoparticles or nanocolloids with egg Nem diameter of preferably less than 250 nm, especially preferably less than 100 nm. 8. The composition according to at least one of claims 1 to 7, characterized in that it further comprises at least one pharma contains cosmetic and / or cosmetic auxiliary. 9. Pharmaceutical preparation containing the composition according to one of claims 1 to 8. 10. Pharmaceutical preparation according to claim 9, characterized records that they continue to have at least one pharmaceutical Contains active ingredient. 11. Pharmaceutical preparation according to claim 9, characterized records that they ent vitamin C and / or one of its derivatives holds. 12. Pharmaceutical preparation according to one of claims 9 to 11, characterized in that they incorporate the composition  processed in gelatin, such as hard or soft gelatin capsules holds. 13. Use of the pharmaceutical preparation according to one of the Claims 9 to 12 for lowering the ATP and / or cAMP mirror. 14. Use of the pharmaceutical preparation according to one of the Claims 9 to 12 for the prophylaxis and / or therapy of cancer diseases. 15. Use of the pharmaceutical preparation according to one of the Claims 9 to 12 for immune stimulation. 16. Use of the pharmaceutical preparation according to one of the Claims 9 to 12 for the prophylaxis and / or therapy of Gammopa thien, immunodeficiency and autoimmune diseases. 17. Cosmetic preparation containing the composition according to one of claims 1 to 8. 18. Cosmetic preparation according to claim 17, characterized records that they incorporated the composition in gelatin, e.g. B. hard or soft gelatin capsules. 19. The composition according to any one of claims 1 to 8, characterized characterized in that they contain other substances, such as dyes, contains or stored. 20. Use of the composition according to claim 19 for dyeing and / or conditioning textiles, leather or paper. 21. Use of the composition according to one of claims 1 to 8 for the production of a finely dispersed system. 22. Use of the composition according to one of claims 1 to 8 as an additive to the dialysis fluid in hemodialysis.   23. A method for producing a finely dispersed system comprising the composition according to at least one of claims 1 to 8, comprising the steps

• a) pressure filtration, preferably sterile filtration, the composition and / or
• b) Mixing or stirring or homogenizing the composition with commercially available devices.