HK1134458A - Dispersions of nanoureas containing active ingredients - Google Patents

Description

Dispersions of nanoureas containing active ingredients

The invention relates to dispersions of nanoureas containing active compounds, to a method for the production thereof and to the use thereof.

Coating plastics with active compounds is generally not successful because the active compounds are not compatible with the plastics and therefore do not bond together homogeneously. Local differences in the concentration of active compound are a major drawback, since this creates areas which are inert and free of active compound. Furthermore, in the case of non-uniform bonding, the mechanical properties of the plastic are also very adversely affected.

If the plastics are modified by dissolving the active compound and mixing it with the (optionally likewise dissolved) plastics, this process has the following disadvantages; on the one hand, no suitable solvents for both active compounds and plastics can be found; on the other hand, the use of organic solvents is disadvantageous in principle, in particular because solvent residues may remain in the product, which is unacceptable for, for example, medical-technical articles.

Coating plastics with active compounds is, however, also important, in particular in the field of medical technology. For example, bacterial colonization of medical technology articles such as catheters is a very serious problem, as this is often the initial step after the patient being treated for a severe infection. Thus, many methods have been proposed for antimicrobial coating of catheters, either by coating the catheter material itself (e.g., silicone, polyurethane, latex or PVC) or by coating with an antimicrobial active material. As antimicrobially active coatings, it has been proposed, for example, to deposit pure metal layers doped with silver (US 5,320,908, US 5,395,651 and US 5,965,204); however, these (brittle) coatings have poor adhesion to the catheter material. Specific inorganic glass coatings have also been proposed which release Ag, Cu or Zn ions as a result of glass hydrolysis (US6,143,318). Also proposed are mixtures of Ag salts with sulfonamides (US 4,581,028) or triclosan (WO2000/57933), and the use of metal colloids. However, in addition to the disadvantages already described, all the above-mentioned coatings have the following disadvantages: the release of the active compound (e.g. the Ag ions) is not stable over time, i.e. the Ag ions are released very rapidly at the beginning and then decrease substantially, losing antimicrobial activity. Compensation by an appropriate increase in the initial active compound concentration is not feasible, since this can lead to adverse side effects. Thus, for example, for catheters, frequent replacement is required to reduce microbial contamination.

DE-A69734168 describes implants with cavities which contain active compounds and slowly release these active compounds. This form of packaging is very complex and the implant must be placed by means of surgical intervention. Application of this solution to coatings or plastics is not feasible with this type of macroscopic "slow release" system.

In DE-A102004030504, the use of pH-sensitive polymers for the coating of macroscopic oral pharmaceutical forms for selective active compound release is described. This application is limited to certain areas where the release of the active compound is caused by selectively changing the pH in the environment.

In DE-A69819145, biodegradable polymers are used to encapsulate active compounds. The problem is the lack of stability of such compounds in aqueous systems due to their susceptibility to hydrolysis or microbial degradation.

DE 4122591 describes water-insoluble polymer particles which are dispersed in water and coagulated with a gelling agent. And then dried to obtain polymer pellets. The disadvantage is that the preparation process is very complicated and the microparticles are incompatible with many additives of galenic formulations (galenics), such as surfactants or ionically charged polymers.

DE 19930795 describes the encapsulation of active compounds by diffusion into polymer beads having a diameter of 50 to 2000 μm. The use of polylactates also results in systems that are unstable when stored in the presence of moisture and are not stable against microorganisms.

In EP 0429187, sustained release formulations of cross-linked polyvinylpyrrolidone are described, which contain a certain type of steroid, which delays release. The described methods are limited to the use of certain classes of steroids.

All the systems described are suitable only for specific application systems and certain classes of active substances. No method is described which is capable of covering a broad spectrum of active compounds. Furthermore, the production of the individual systems is often complicated and in some cases the solvents used cannot be completely separated off. There is no description of incorporation into plastics or coatings.

The preparation of aqueous nanourea dispersions containing urea particles with a particle size of 10 to 400 nm is known in principle and is described, for example, in WO 2005/063873. In this process, hydrophilicized polyisocyanates are added to water in the presence of catalysts, so that crosslinking occurs in the substantially dispersed particles via urea bonds. There is no description in this document of the degree of compatibility of such dispersions with active compounds and/or whether they can be used to modify plastics, exhibiting controlled release behaviour with respect to the active compounds contained.

It is therefore an object of the present invention to make available plastic matrices which are compatible with active compounds, from which coatings and materials and molding materials can be prepared which exhibit "controlled-release behavior", i.e. controlled release characteristics, optionally with a delay in release over a period of time.

It has now been found that this object can be achieved by specific nanourea dispersions which contain the active compound to be released.

The present invention therefore relates to a process for preparing aqueous nanourea dispersions containing active compounds, in which:

A) the nanoureas are formed by reacting hydrophilized polyisocyanates in aqueous medium to form the urea structure-NH-C (O) -NH-, wherein,

B) at least one active compound is added before, during or after urea formation in A.

Active compounds are defined hereinafter as elements or chemicals that have an effect on biological systems, in particular on prions, viruses, bacteria, cells, fungi and organisms.

Examples are biocidally active compounds having, for example, a pesticidal, fungicidal, algicidal, insecticidal, herbicidal, spermicidal, parasiticidal, antibacterial (destroying bacteria), bacteriostatic, antibiotic, antifungal (destroying fungi), antiviral (destroying viruses), virucidal and/or antimicrobial (destroying microorganisms) action. Combinations of active compounds and, for example, with excipients, binders, neutralizing agents or additives are also possible. Other active compounds and combinations, for example from the human or veterinary field, may also be used.

As hydrophilicized polyisocyanates it is possible to use all nonionically, (potentially) anionically or (potentially) cationically hydrophilicized NCO group-containing compounds known per se to the person skilled in the art. Preferably, the hydrophilicized polyisocyanates have at least one non-ionically hydrophilicized structural unit. It is particularly preferred that the hydrophilization of the polyisocyanates is effected exclusively by means of the nonionically hydrophilicizing groups.

These nonionically hydrophilicizing groups are preferably introduced into the polyisocyanates by reaction with polyethers which are preferably monofunctional with respect to the groups which are reactive toward NCO groups. Examples of such NCO-reactive groups are hydroxyl, mercapto (thiol) or amino functions. In principle, however, these polyethers can also contain more than one NCO-reactive group.

The polyethers described above for the hydrophilization are generally polyoxyalkylene ethers in which preferably from 30 to 100% by weight of the oxyalkylene units are oxyethylene groups and up to 70% by weight are oxypropylene units.

Particularly preferably, they are polyoxyalkylene ethers of the above-mentioned kind which contain from 5 to 70, preferably from 7 to 55, oxyethylene groups per molecule (based on a statistical average).

Such polyethers can be prepared by methods known per se by alkoxylation of suitable starter molecules (for example in Ullmanns encyclopedia of Industrial Chemistry, Ullmann's encyclopedia of Industrial Chemistry, 4 th edition, volume 19, Verlag Chemistry, Weinheim, pages 31-38).

For example, suitable starter molecules are: saturated monoalcohols, for example methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, the isomeric pentanols, the isomeric hexanols, the isomeric octanols, the isomeric nonanols, n-decanol, n-dodecanol, n-tetradecanol, n-hexadecanol, n-octadecanol, cyclohexanol, the isomeric methylcyclohexanols or hydroxymethylcyclohexane, 3-ethyl-3-hydroxymethyloxetane or tetrahydrofurfuryl alcohol; diethylene glycol monoalkyl ethers such as diethylene glycol monobutyl ether; unsaturated alcohols, such as allyl alcohol, 1-dimethylallyl alcohol or oleyl alcohol; aromatic alcohols, such as phenol, the isomeric cresols or methoxyphenols; araliphatic alcohols, such as benzyl alcohol, anisyl alcohol or cinnamyl alcohol; secondary monoamines, such as dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, bis (2-ethylhexyl) amine, N-methyl-and N-ethylcyclohexylamine or dicyclohexylamine; heterocyclic secondary amines, for example morpholine, pyrrolidine, piperidine or 1H-pyrazole. Preferred starter molecules are saturated monoalcohols. Particular preference is given to using methanol, butanol and diethylene glycol monobutyl ether as starter molecules.

Alkylene oxides suitable for the alkoxylation reaction are, in particular, ethylene oxide and propylene oxide, which can be used in any desired sequence or in the form of mixtures in the alkoxylation reaction.

Hydrophilicized polyisocyanates are based on the aliphatic, cycloaliphatic, araliphatic and aromatic polyisocyanates known per se to the person skilled in the art, which contain more than one NCO group per molecule and have an isocyanate content of from 0.5 to 50% by weight, preferably from 3 to 30% by weight, more preferably from 5 to 25% by weight, or mixtures thereof.

Examples of suitable polyisocyanates of this type are butane diisocyanate 1, 4-butane diisocyanate, cyclohexane-1, 3-and 1, 4-diisocyanate, 1, 6-Hexamethylene Diisocyanate (HDI), 1-isocyanato-3, 3, 5-trimethyl-5-isocyanatomethylcyclohexane (isophorone diisocyanate, IPDI), 2, 4, 4-trimethyl-1, 6-hexamethylene diisocyanate, isocyanatomethyl-1, 8-octa-diisocyanate, methylenebis (4-isocyanatocyclohexane), tetramethylxylylene diisocyanate (TMXDI) or triisocyanatononane (TIN, 4-isocyanatomethyl-1, 8-octa-diisocyanate), and optionally also in mixtures with other diisocyanates or polyisocyanates. In principle, aromatic polyisocyanates, such as 1, 4-phenylene diisocyanate, 2, 4-and/or 2, 6-Tolylene Diisocyanate (TDI), diphenylmethane 2, 4 ' -and/or 4, 4 ' -diisocyanate (MDI), triphenylmethane 4, 4 ' -diisocyanate, 1, 5-naphthylene diisocyanate are also suitable.

In addition to the polyisocyanates mentioned above, it is also possible to use higher molecular weight secondary products having uretdione (uretdione), isocyanurate, urethane, allophanate, biuret, iminooxadiazinedione and/or oxadiazinetrione structures. Such secondary products are prepared in accordance with known methods by modification of monomeric diisocyanates, which are known and described, for example, in Laas et al, J.prakt.chem., 336, 1994, 185-200.

Preferably, the hydrophilicized polyisocyanates of component A) are based on polyisocyanates or polyisocyanate mixtures of the above-mentioned type having exclusively isocyanate groups bound to aliphatic or cycloaliphatic groups or any combination thereof.

Particularly preferred hydrophilicized polyisocyanates are those based on 1, 6-hexamethylene diisocyanate, isophorone diisocyanate or the isomeric bis (4, 4' -isocyanatocyclohexyl) methanes, and also mixtures of the abovementioned diisocyanates.

Catalysts may additionally be used for the preparation of the nanourea dispersions. Suitable catalysts are, for example, tertiary amines, tin compounds, zinc compounds or bismuth compounds, or basic salts.

Suitable tertiary amines are triethylamine, tributylamine, dimethylbenzylamine, dicyclohexylmethylamine, dimethylcyclohexylamine, N, N, N ', N ' -tetramethyldiaminodiethyl ether, bis (dimethylaminopropyl) urea, N-methyl-and N-ethylmorpholine, N, N ' -dimorpholinodiethyl ether (DMDEE), N-cyclohexylmorpholine, N, N, N ', N ' -tetramethylethylenediamine, N, N, N ', N ' -tetramethylbutanediamine, N, N, N ', N ' -tetramethylhexane-1, 6-diamine, pentamethyldiethylenetriamine, dimethylpiperazine, N-dimethylaminoethylpiperidine, 1, 2-dimethylimidazole, N-hydroxypropylimidazole, 1-azabicyclo- (2, 2, 0) -octane, 1, 4-diazabicyclo- (2, 2, 2) -octane (Dabco) and alkanolamine compounds, such as triethanolamine, triisopropanolamine, N-methyl-and N-ethyldiethanolamine, dimethylaminoethanol, 2- (N, N-dimethylaminoethoxy) ethanol, N ', N-tris (dialkylaminoalkyl) hexahydrotriazine, for example N, N', N-tris (dimethylaminopropyl) -s-hexahydrotriazine, iron (II) chloride, zinc chloride or lead octoate.

Preference is given to tertiary amines of the abovementioned type, tin salts, such as tin dioctoate, tin diethylhexanoate, dibutyltin dilaurate and/or dibutyltin dilaurylsulfaptide, 2, 3-dimethyl-3, 4,5, 6-tetrahydropyrimidine, tetraalkylammonium hydroxides, such as tetramethylammonium hydroxide, alkali metal hydroxides, such as sodium hydroxide, alkali metal alkoxides, such as sodium methoxide and potassium isopropoxide, and/or alkali metal salts of long-chain fatty acids having from 10 to 20 carbon atoms and optionally having pendant hydroxyl groups.

Particularly preferred catalysts are tertiary amines, triethylamine, ethyldiisopropylamine and 1, 4-diazabicyclo [2, 2, 2] octane.

These catalysts are generally used in amounts of from 0.01 to 8% by weight, preferably from 0.05 to 5% by weight, more preferably from 0.1 to 3% by weight, based on the total solids content of the resulting dispersion. Mixtures of catalysts may also be added.

Solvents such as N-methylpyrrolidone, N-ethylpyrrolidone, methoxypropyl acetate, dimethyl sulfoxide, methyloxypropyl acetate, acetone and/or methyl ethyl ketone may be added to the mixture. After the reaction and dispersion have ended, volatile solvents such as acetone and/or methyl ethyl ketone can be removed by distillation. The preparation is preferably carried out without solvent and with acetone or methyl ethyl ketone; more preferably, the preparation is carried out in the absence of a solvent.

To prepare the dispersion, the hydrophilicized polyisocyanates described above are dispersed in an aqueous medium, optionally in the presence of a catalyst.

The dispersion and reaction are preferably carried out by the following method: thorough mixing is carried out with stirrers or other types of thorough mixing methods, such as recirculation, static mixers, spike mixers (spike mixers), jet dispersers, rotors or stators, or mixing under the action of ultrasound.

In principle, the NCO groups can be modified with isocyanate-reactive compounds, such as primary or secondary amines, and/or (poly) alcohols, during or after the dispersion.

Preferably, the molecular ratio of NCO groups of the hydrophilicized polyisocyanate to water is from 1:100 to 1:5, more preferably from 1:30 to 1: 10.

In principle, the hydrophilicized polyisocyanates can be dispersed in water all at once. The hydrophilicized polyisocyanate can also be added continuously over a period of, for example, 30 minutes to 20 hours. However, preference is given to addition in portions, the number of portions being from 2 to 50, preferably from 3 to 20, more preferably from 4 to 10, the size of the individual portions being able to be identical or different.

The waiting time between the batches is generally 5 minutes to 12 hours, preferably 10 minutes to 8 hours, more preferably 30 minutes to 5 hours.

It is also preferred to add the hydrophilicized polyisocyanate continuously over a period of from 1 hour to 24 hours, preferably from 2 hours to 15 hours.

In the preparation of urea granules, the temperature of the vessel is generally in the range of from 10 to 80 ℃, preferably from 20 to 70 ℃, more preferably from 25 to 50 ℃.

Preferably, after the reaction of the hydrophilized polyisocyanate with water, the reactor is evacuated at an internal temperature of from 0 ℃ to 80 ℃, preferably from 20 ℃ to 60 ℃, more preferably from 25 ℃ to 50 ℃. The evacuation treatment is carried out until an internal pressure of 1 to 900 mbar, preferably 10 to 800 mbar, more preferably 100 and 400 mbar is reached. The duration of degassing after the actual reaction is usually 1 minute to 24 hours, preferably 10 minutes to 8 hours. It is also possible to carry out the degassing treatment by raising the temperature without evacuation.

Preferably, the nanourea dispersion is thoroughly mixed by, for example, stirring while the vacuum is pulled.

The solids content of the urea particles present in the dispersion obtained according to A) is generally from 10 to 60% by weight, preferably from 20 to 50% by weight, more preferably from 30 to 45% by weight.

The addition of the active compound can be carried out during or after the preparation of the granules. Thus, the reactive compounds can be present even during the dispersion of the hydrophilicized polyisocyanates, or metered in parallel during this process, or added after the preparation of the particles. The absorption of the active compound in the particles takes place at least partially in the process. This absorption inside and/or on the surface of the particles leads to a time-distributed release profile of the active compound.

If the added active compound is not completely dissolved or absorbed in the dispersion, the residual active compound can be removed by separation, for example by filtration.

In order to remove the active compounds dissolved in the dispersion water which are not bound to the nanoureas, the low molecular weight constituents of the dispersion are removed according to methods known per se, for example by dialysis or ultrafiltration. Here, the specific exclusion limit of the membrane is selected in accordance with the hydrodynamic volume of the dissolved active compound. Preferred exclusion limits are less than 1000000 daltons (═ g/mole), more preferably less than 100000 daltons (═ g/mole).

The amount of active compound is generally from 0.0001 to 50% by weight, preferably from 1 to 20% by weight, more preferably from 5 to 15% by weight, based on the solids content of the urea particles present. The amount of active compound generally depends on the amount of the particular active compound required for the particular specification.

Preferably, the poorly or completely water-insoluble active compounds in water are mixed with the hydrophilicized polyisocyanates, optionally via cosolvents, and then dispersed in the aqueous medium. Preferably, however, these reactive compounds do not contain NCO-reactive groups, or if they do contain such groups, the urea-forming reaction must be designed so that no significant reaction of the NCO groups with the reactive compounds takes place. If a solvent is used for the addition of the active compound, it is preferred to remove the solvent by distillation after the addition of the active compound.

During the addition of the active compound, the temperature is preferably from 25 to 100 ℃.

In the process according to the invention, it is of course also possible to use excipients and additives, such as stabilizers, surfactants, solubilizers, neutralizing agents, active group scavengers, flow aids and/or free-radical scavengers.

The dispersions obtainable by the process according to the invention and the active compound-containing nanosized urea particles contained in the dispersions are a further object of the invention.

The average particle size of these nanourea particles, measured by laser correlation spectroscopy, is in the range of 10 to 300 nm, preferably 20 to 150 nm.

These nanourea dispersions containing active compounds can also be dried by methods customary per se in the industry, for example by distillation, freeze drying or spray drying.

The dispersions obtained according to the invention and the particles contained in the dispersions are valuable starting materials for the production of coatings, materials and moldings comprising reactive compounds, preferably based on polyurethanes.

For incorporation into coating formulations, nanourea dispersions containing active compounds can be used as such, especially if the coating formulation itself contains ingredients such as binders dispersed in water.

However, it is also possible to dry the dispersion and add it as a solid to the nanourea containing the active compound. It is also possible to add the active compounds in the solvent to the nanoureas.

Preferred binders in such coating formulations are polyurethanes of various types, poly (meth) acrylates, polyesters and silicones. Particularly preferred are polyurethanes which can be used in the form of aqueous dispersions, solutions in organic solvents or solvent-free formulations. One-component and two-component polyurethanes can likewise be used here.

The coating formulation can be applied to the article by any desired method, such as spraying, vaporizing, brushing, dipping, pouring (flooding) or by roller and doctor blade. Suitable substrates are, for example, metals, plastics, in particular polyethylene, polypropylene, polytetrafluoroethylene, polyurethane, silicone, polyvinyl chloride, poly (meth) acrylate, polycarbonate, polyester, wood, materials, textiles or glass. Application and drying and/or hardening of the coating formulation may be carried out before, during or after formation of the article. Drying and/or hardening is carried out at room temperature or at elevated temperature, optionally under reduced pressure.

Materials and molded articles which can be produced by means of the particles and dispersions according to the invention or which can be coated with coatings comprising the particles according to the invention are all articles of daily use known per se, in which exposure to microorganisms is brought about by frequent contact, for example with any type of handle, but articles for storage, transport (for example tubes) or treatment of liquid media are also to be understood as being within the abovementioned range. However, articles from the medical technology field such as catheters, tubes, containers, apertures, implants, artificial organs (both in vitro and in vivo), prostheses, vascular prostheses (stents), vision aids (e.g. contact lenses), endoscopes and wound coverings are preferred.

Example (b):

all percentages are by weight unless otherwise indicated.

Unless otherwise indicated, all analytical measurements refer to temperatures at 23 ℃.

The reported viscosity was determined by rotational viscosity measurement according to DIN 53019 at 23 ℃ using an rotational viscometer from engpu corporation of Anton PaarGermany GmbH, Ostfildern, DE.

The NCO content was determined volumetrically in accordance with DIN-EN ISO 11909, unless otherwise stated.

The reported particle size was determined from laser correlation spectroscopy (instrument: Malvern Zetasizer 1000, Malvern Inst. Limited).

The solids content was determined in accordance with DIN-EN ISO 3251.

By infrared spectroscopy (at 2260 cm)^-1Band) was detected for free NCO groups.

The concentration of silver ions was determined by spectroscopic analysis according to DIN ISO 17025.

Use ofIs/are as followsFloating dialysis tube (floating dialysis tubes). The tube material was a cellulose ester film with a nominal exclusion limit of 25000 grams/mole. The membrane was washed with deionized water prior to use and conditioned in a water bath.

Chemical product

VP LS 2336: hydrophilicized polyisocyanates based on 1, 6-hexamethylene diisocyanate, which are solvent-free, have a viscosity of about 6800mPa s and an isocyanate content of about 16.2%, from Bayer MaterialScience AG, Leverkusen, DE, Leverkusen, Germany.

DLN: anionically hydrophilized uncrosslinked fatsAqueous dispersions of polyester polyurethanes, solids content of about 40%) Bayer materials science, Levokusen, Germany.

16: antifoams from Pittsfe chemical company of Hildes Hehm, Germany (Petrofer-Chemie, Hildesheim, DE).

Other chemicals were purchased from the fine chemicals department of Sigma Aldrich GmbH, Taufkirchen, DE, te.

Active compound (b):

	active compound	Active compound content	Source
				1	Ciprofloxacin	100％	Bayer health Care company, Leverkusen, Germany (Bayer health Care AG, Leverkusen, DE)
2	Acetylsalicylic acid	100％	Sigma-Adreoch company of Teken, Germany
				3	Salicylic acid	100％	Sigma-Adreoch company of Teken, Germany
4	Silver nitrate	100％	Sigma-Adreoch company of Teken, Germany
				5	1-Hexadecylpyridinium chloride	100％	Sigma-Adreoch company of Teken, Germany
6	Hyamine 1622	100％	Sigma-Adreoch company of Teken, Germany
				7	Preventol D7	14％	Formulations of isothiazolones, Lanksi, Leverkusen, Germany (Lanxess AG, Leverkusen, DE)
8	Potassium iodide-iodine complex	50％	Prepared by mixing equimolar amounts of potassium iodide and iodine in water, both chemicals being from Sigma-Aldrich of tekh, Germany
				9	Propyl p-hydroxybenzoate	100％	Sigma-Adreoch company of Teken, Germany
10	Hexamethoxymethyl melamine	84％	Sigma-Adreoch company of Teken, Germany

11	Urotropine	100％	Sigma-Adreoch company of Teken, Germany
				12	4-hydroxybenzophenones	100％	Sigma-Adreoch company of Teken, Germany
13	Curcumin (curcumin)	100％	Sigma-Adreoch company of Teken, Germany
				14	Preventol R50	50％	Benzalkonium chloride, Lankangsi, Lewakusen, Germany
15	Preventol O extra	100％	Sodium 2-phenylphenol, Lankangsi Lewakusen, Germany
				16	Preventol SB extra	100％	N- (4-chlorophenyl) -N' - (3, 4-dichloro-phenyl) urea, Lankangsi, Lewakusen, Germany
17	Preventol CMK troche	100％	4-chloro-3-methylphenol, Lancex, Lewakusen, Germany
				18	Glutaraldehyde	50％	Sigma-Adreoch company of Teken, Germany
19	Formaldehyde (I)	37％	Sigma-Adreoch company of Teken, Germany
				20	Camphor (racemic)	100％	Sigma-Adreoch company of Teken, Germany
21	Menthol (racemic)	100％	Sigma-Adreoch company of Teken, Germany

Example 1

Preparation of active compound-free nanourea dispersions

820.20 g were added to a solution of 20.72 g triethylamine in 4952 g deionized water at 30 deg.C with vigorous stirringVP LS2336, then 0.32 gAnd 16, continuing stirring. After 3, 6 and 9 hours, 820.20 g were addedVP LS2336, then 0.32 g of Isofloam 16 were added separately and the mixture was stirred for a further 4 hours at 30 ℃. The reaction mixture was then stirred under a vacuum of 200 mbar at a temperature of 30 ℃ for a further 3 hours, and the resulting dispersion was bottled.

The resulting white dispersion had the following properties:

solid content: 40 percent of

Particle size (LKS): 83 nm

Viscosity (viscometer, 23 ℃): <50mPas

pH(23℃)： 8.33

Charge determination: total charge 57 + -6 mu eq/g, surface charge 15 + -1 mu eq/g

Zeta potential(pH＝8)：24.9±1.0

Example 2

Subsequent loading of the nanoureas with active compounds

To prepare the nanourea dispersions containing active compound, in each case 50 g of the nanourea dispersion from example 1 are treated with an amount of active compound 1 to 21 such that the concentration of active compound obtained is approximately 3%, based on the solids content. The mixture was stirred vigorously by a magnetic stirrer for 18 hours. After filtering the resulting dispersion, 10 ml of each of the resulting samples were loaded into dialysis tubes and dialyzed twice (for about 22 hours) each with about 1 l of deionized water. Samples were taken from the dialysis tubing by pipette for active compound testing.

Example 3

Preparation of nanoureas in the Presence of active Compounds

410 g of the mixture was mixed in a reaction vessel with stirringVP LS2336 and 41.0 g camphor. Then, 1058 grams of deionized water was added to disperse the mixture at about 23 ℃ with vigorous stirring, and treated with 0.04 grams of isofloam 16 and 2.59 grams of triethylamine. Then, a vacuum of 200 mbar was immediately applied and the mixture was stirred for about 10 hours; the temperature rises by about 30% C during this process. The resulting dispersion was bottled.

The resulting white dispersion had the following properties:

solid content: 27 percent of

Particle size (LKS): 93 nm

Viscosity (viscometer, 23 ℃): <50mPas

pH(23℃)： 6.98

Example 4

Preparation of nanoureas in the Presence of active Compounds

The procedure as described in example 3 was followed except that racemic menthol was used instead of camphor.

The resulting white dispersion had the following properties:

solid content: 28 percent of

Particle size (LKS): 86 nm

Viscosity (viscometer, 23 ℃): <50mPas

pH(23℃)： 7.90

Example 5

The antibacterial effect of the nanourea dispersions loaded with active compound was tested.

Cells of Staphylococcus epidermidis (Staphylococcus epidermidis)498 and Bacillus subtilis 168 were seeded on agar plates and after incubation at 37 ℃ overnight, a visible lawn of cells was formed on the agar. Agar contains a nutrient-rich medium (Muller-Hinto medium, OD)₆₀₀The set value is 0.1; 200 microliters of each plate was inoculated and dried at room temperature for 1 hour). A small hole is drilled in the center of each plate. Into this well was charged a nanourea dispersion (100. mu.l) containing the active compound, prepared analogously to example 2, in which the active compound was present only in bound form. After overnight incubation, the agar was examined for diffusion of the antibiotic active compound and the disappearance of the cellular lawn around the drilled wells was observed ("zone of inhibition"). These inhibition zones are compared with agar plates without other additives and with agar plates containing nanourea dispersions without active compound.

Table: diameter of the inhibition zone, micrometer [ minus diameter of drilled orifice for application of active Compound ] (C-E: dispersion of example 2, B: dispersion of example 1)

It can be seen that the nanourea dispersions (C-E) modified with active compounds have an antimicrobial effect compared to the control experiments A and B.

Furthermore, the active compound-loaded nanourea dispersions according to the invention have a controlled-release behavior based on the active compounds contained in the dispersion in bound form. It can be seen from the antimicrobial effect measured that, because of the previous dialysis treatment, the dispersion used no longer contained any free unbound active compound, but the antimicrobial effect was only produced by the re-release of bound active compound.

Example 6

The antibacterial effect of the nanourea dispersions loaded with active compound was tested.

The test according to example 5 was performed in an overnight culture of staphylococcus epidermidis (ATC 14990). The following active compound-loaded dispersions F-K were prepared analogously to example 2. As comparative examples L-O, aqueous solutions having various ciprofloxacin (Cipro) concentrations were additionally tested.

Experiment of	Active compound	Inhibition zone, micron Staphylococcus epidermidis (ATC 14990)
			F	Acetylsalicylic acid	13
G	Salicylic acid	38
			H	Potassium iodide-iodine complex	14
I	Hexamethoxymethyl melamine	13
			J	Preventol R 50	36
K	Formaldehyde (I)	21
			L	Cipro 1mM	43
M	Cipro 0.1mM	36
			N	Cipro 0.01mM	26
O	Cipro 0.001mM	11

Example 7

Test for determining the delayed Release (sustained Release Properties) of active Compounds

a) 900 g each of the nanourea dispersions from example 1 were treated with 36 g of silver nitrate in a beaker with stirring. The dispersion was stirred at room temperature for 24 hours and then stored in a closed bottle for 5 months.

1.04 g (equivalent to 0.04 g silver nitrate) of this mixture was added to 40 g Impranil DLN with stirring (80 min). Then, a film was formed on the glass plate using a doctor blade (gap: 210 μm), and dried at room temperature for 1 hour. The film was peeled off and 3 cm × 3 cm pieces were cut from the center. The cut film was placed in 10 ml of deionized water in a bottle with a screw cap so that the water flowed completely around the film. After 24 hours, the water was changed to separate the silver ions attached to the surface.

The water was then replaced with new deionized water after 3, 7 and 51 days, respectively (from the first water exchange), and the concentration of silver ions was analyzed in each case.

b) Similar to the procedure of a), but a mixture of silver nitrate and nanourea dispersion was freshly prepared and used directly after 24 hours of mixing.

c) Comparative experiment) similar to the procedure of a), but instead of using a mixture of silver nitrate and nanourea dispersion, 0.04 g of silver nitrate was mixed directly into the Impranil DLN dispersion.

Table: extraction Curve of silver ions [ Ag extracted per kg of extraction solution ] determined by the concentration of silver ions⁺Divided by the number of days in each extraction stage]

	3 days	7 days	51 days
				a)	0.1450	0.0525	0.0295
b)	0.1800	0.0525	0.0319
				c) (comparison)	0.1400	0.1225	0.0113

It can be seen that for the same amount of mixed silver ions, the amount of released silver ions decreased significantly at a faster rate in the case of comparative experiment c) without nanourea addition than in the case of nanourea addition. Only about one third of the silver ions were released in comparative experiment c) compared to experiments a) and b) over a period of 7 to 51 days. This shows that the antibacterial action in comparative experiment c) is significantly reduced compared to experiments a) and b). In experiments a) and b) the desired delayed release of silver nitrate ions was achieved.

Claims (14)

1. A process for preparing an aqueous nanourea dispersion containing an active compound, wherein:

A) the nanoureas are formed by reacting hydrophilized polyisocyanates in aqueous medium to form the urea structure-NH-C (O) -NH-, wherein,

B) adding at least one active compound before, during or after urea formation in A).

2. The method of claim 1, wherein the aqueous medium in a) is an aqueous mixture comprising at least 95% by weight water.

3. The process according to claim 1 or 2, wherein the hydrophilicized polyisocyanate is a nonionically hydrophilicized polyisocyanate.

4. A process according to any one of claims 1 to 3, characterised in that the hydrophilised polyisocyanate is based on a polyisocyanate having exclusively aliphatically or cycloaliphatically bound isocyanate groups, or any mixture thereof.

5. A process according to any one of claims 1 to 4, characterised in that a catalyst is also used in the urea formation.

6. The method of claim 5, wherein the catalyst is a tertiary amine.

7. The process according to any one of claims 1 to 6, wherein the hydrophilicized polyisocyanate has a molar ratio of NCO groups to water of from 1:30 to 1: 10.

8. The process according to any one of claims 1 to 7, wherein in A) the hydrophilicized polyisocyanate is added in portions to the aqueous medium.

9. A process as claimed in any one of claims 1 to 8, characterized in that the active compound which is not bound to the dispersion is subsequently removed from the dispersion.

10. The process according to any one of claims 1 to 9, wherein the amount of active compound is calculated such that in the dispersion loaded with active compound the bound active compound content is from 5 to 15% by weight, based on the total solids content of the dispersion.

11. A dispersion obtainable by the process of any one of claims 1 to 10.

12. Nanourea particles having an average particle size of 10-300 nm as measured by laser correlation spectroscopy, characterized in that the nanourea particles comprise an active compound.

13. The nanourea particles of claim 12, having an active compound concentration of 5 to 15% by weight.

14. Coating formulations, coatings, materials and molded articles obtained using the dispersion as claimed in claim 11 or the particles as claimed in claim 12 or 13.