DE10214226B4 - Drug carrier, process for its preparation and use - Google Patents

Abstract

Drug carrier with a produced by supercritical drying hydrophilic metal oxide airgel or silica airgel
characterized in that
the spatial structure of the airgel (2) is loaded with at least one active substance (1), the loading of the active substance being carried out by means of a supercritical gas in which the active substance (1) is dissolved, and
wherein the spatial structure with water or an aqueous electrolyte solution as a solvent (10) for release at the site of action of at least one active substance (1) is destructible.

Description

The The present invention relates to a drug carrier according to claim 1, a method for the preparation of the drug carrier according to claim 12 and a use of the active ingredient carrier according to Claim 9.

The Effects and side effects of drugs such. B. drugs or odors are mostly dependent on the speed and the extent of her Appearing at the site of action. For drugs z. B. bioavailability. The adsorption of an active substance in the body requires the previous one Release from a drug form into a dissolved form. It is therefore one Goal, the existing drugs in a therapeutically optimal To offer dosage form.

A of many possibilities is to control the release of the drug in the body the use of so-called adjuvants. Excipients are defined as substances that make it possible Drugs or substances with special properties (both together referred to herein as active ingredients) in a corresponding To bring preparation form and which are further suitable, to improve the properties of a dosage form. To excipients belong also the carrier materials, which are themselves no active ingredients, but only serve the corresponding Absorb active substances and in the body release again. The active ingredients are in one way or another on the carrier material brought or solved in: Embedding and scaffolding medicines.

Of the Difference between the two forms is that of a porous insoluble and indigestible matrix existing scaffold tablets through the drug solvent and diffusion processes while preserving the original Release the form and size of the tablet, while the most porous preparations prepared according to the embedding principle (Capsules, disintegrating tablets or erosion tablets). The active substance is in this case by diffusion from the individual particles Approved.

Thereby the release mechanism is also affected. Depending on the desired Release mechanism (fast or delayed release) will be different excipient used. The following substances are mentioned as examples: fats, partial glycerides, Waxes, polyacrylates, lactose, starches. As a porous substance carrier is often fumed silica (Aerosil) used. By applying of the active ingredient on the porous carrier becomes his surface greatly enlarged. This usually improves the release kinetics.

From the US Pat. No. 6,280,744 B1 is known, an inorganic airgel in connection with drugs such. B. to use in pharmacy. An airgel is loaded with an active substance in a liquid solvent. In such a process, only aerogels can be used whose spatial structure is not destroyed during the subsequent drying at normal pressure and T> T _space . This would only be possible with aerogels produced by subcritical drying. Such aerogels or their production processes are in the WO 96/26890 A2 described and are in the US Pat. No. 6,280,744 B1 used. These aerogels have a relatively high density (> 0.1 g / cm ³ ) and low specific surface area (~ 400-500 m ² / g, see WO 96/26890 A2 ), compared with the aerogels produced by supercritical drying (density 0.003-0.1 g / cm ³ , surface area up to 1000 m ² / g, see eg. WO 92/03378 A1 ). After the in US Pat. No. 6,280,744 B1 The loading process used breaks down the structure of the aerogels produced by supercritical drying. This applies in particular to hydrophilic aerogels when in contact with liquid water. After the subsequent drying under the conditions in US Pat. No. 6,280,744 B1 are described, the powder (or a powdered xerogel) with the density> 0.1 g / cm ³ and significantly lower surface area and porosity is obtained.

adversely is that after drying still residues of the solvent contained in the powder. This is medical, hygienic or for taste reasons undesirable. Also, by solving in the liquid solvent destroyed the three-dimensional structure of the airgel with its high porosity. In order to loses the airgel a part of its valuable properties.

The WO 96/25850 A1 relates to the use of aerogels as a carrier material for active substances in agricultural and / or veterinary fields. The active compounds are applied either in dissolved form and / or in a liquid carrier medium in suspended form to the aerogels, whereby a quasi-liquid state is retained in the previously formed cavities of the aerogels.

The WO 96/25950 A1 relates to the use of inorganic aerogels as adjuvant and / or Trä germaterial for pharmaceutical agents and / or preparations.

The The object of the present invention is to provide a drug carrier Airgelbasis provide that contains no unwanted solvents and a efficient release of the drug allowed.

These The object is achieved by a drug carrier with the features of the claim 1 solved.

Of the excipient indicates by supercritical Drying produced hydrophilic metal oxide airgel or silica airgel on whose spatial Structure is loaded with at least one active substance, the loading with the active ingredient by means of a supercritical Gases in which the active ingredient dissolved is, takes place and where the spatial Structure that has a high porosity with water or an aqueous electrolyte solution as a solvent for release at the site of action of at least one active ingredient is destructible. In the destruction the spatial Structure of the airgel, the active ingredient is released there very quickly, where it is needed namely at the site of action. The term "place of action" here means the place where a Active substance from the active substance carrier in another system passes. For a drug z. B. the transition to a tissue. Under a solvent become liquids here understood that does not reach the critical point at room temperature to have.

In order to uses the drug carrier according to the invention the very fast destructibility of the airgel in a solvent out, so that the chemical and mechanical properties of the airgel in active, d. H. not as mere Adsorbent, way be used. The airgel takes care of itself its rapid decay for the release of the active ingredient and thus participates actively.

With an airgel according to the invention as a carrier of active substances for the purpose of a defined release of active ingredient Is it possible, exploit a hitherto unnoticed property of the airgel, namely the property that an airgel is virtually a solidified solvent is, d. H. the active substance is spatially in the airgel as in a solvent although fixed in each case as a single molecule (monomolecular).

The inventive principle of the drug carrier is particularly well implemented, if the adsorbent used very fast with the solvent reacts and the adsorbed active ingredients in their position, the they had on the adsorbent, directly from the solvent be recorded. The principle later becomes exemplary for silica Aerogels as adsorbent, water as solvent and organic Substances demonstrated as active ingredients.

at an advantageous embodiment of the drug carrier according to the invention has the airgel on a silicon oxide lattice on. Such aerogels are relative easy to prepare and easy to load with an active ingredient.

One polar or nonpolar solvent has a certain structure together with a substance dissolved in it on, in the molecules, Ions or atoms of the dissolved ones Substance spatially arranged in a certain way around the molecules of the solvent. This spatial conditions are in the airgel with the active ingredient virtually in "solidified form" before.

The Aerogels are made so hydrophilic that they are mixed with the solvent Water react very quickly to a gel-like product, taking the mass of the airgel is very small due to the low density.

Advantageously, the airgel has a bulk density in the range of 0.003 g / ml to 0.3 g / ml. It is also advantageous if the airgel has an inner surface of at least 300 m ² / g and / or a porosity of more than 90%. These aerogels are particularly well suited for loading with active ingredients.

advantageously, the active substance comprises at least one pharmaceutically active substance, a cosmetic substance, a fragrance, a flavoring and / or a color pigment. The active ingredient can thus also be made a combination of different substances, eg. B. one Combination of fragrance and flavor.

It is likewise advantageous if the inventive, rapid and controlled release of the (first) active substance is coupled with a delayed release of a second active substance, which may be identical to the first active ingredient. This may be done with a second drug carrier for sustained release of the second drug and / or in that the second drug is in a form that causes a delayed release of the second drug. By such a design z. B. a depot effect can be achieved in the organism. It is particularly advantageous if the second active ingredient is in crystalline form.

The Task is also performed by a method having the features of the claim 12 solved. The airgel is at supercritical Conditions dried. Already during this drying and / or after that finds the loading of the airgel by adsorption with at least an active ingredient within 0.1 to 20 hours instead. This will be achieved a sufficient concentration of the active ingredient in the airgel.

The inventive method allows the loading of all possible Aerogels, also of aerogels with very low densities, independent of their production process. The structure of the aerogels will be included not impaired. Furthermore the use of all aerogels as a carrier material of active ingredients is made possible. The release is due to the higher porosity improved.

• a) ein Metall-Alkoxid wird mit einer unterstöchiometrischen Menge Wasser und so viel geeignetem Lösungsmittel, dass eine flüssige Phase gebildet wird, mit einem Katalysator zur Reaktion gebracht,
• b) diese Mischung wird anschließend mit so viel Wasser, dass die stöchiometrische Menge erreicht wird, und so viel geeignetem Lösungsmittel versetzt, dass sich eine flüssige Phase bildet und die Zieldichte erreicht wird,
• c) die Mischung aus a) wird einem Druckbehälter zugeführt und mit einer geeigneten Menge Kohlendioxid als Reaktionspartner versetzt,
• d) die Reaktion wird bei Temperaturen von 20–150°C und dem sich aus dem gelösten Kohlendioxid ergebenden Druck zu einem Metalloxid-Gel geführt,
• e) die Reaktionsmischung wird mit einem Metalloxid-Gel ohne Bewegung des Druckbehälters bei Reaktionstemperatur mindestens 1 Stunde, bevorzugt 8–12 Stunden, gealtert und anschließend
• f) wird ein Aerogel hergestellt, indem alle Komponenten außer dem Metalloxid-Gel aus der Reaktionsmischung aus Merkmal d) mit einer überkritischen Substanz extrahiert werden und
• g) anschließend wird mindestens ein Wirkstoff adsorptiv aus einem überkritischen Gas an das entstandene Aerogel gebunden.

The method according to the invention contains the following method steps

• a) a metal alkoxide is reacted with a catalyst with a substoichiometric amount of water and enough solvent to form a liquid phase,
• b) this mixture is then treated with enough water to reach the stoichiometric amount and enough solvent to form a liquid phase and reach the target density,
• c) the mixture of a) is fed to a pressure vessel and admixed with a suitable amount of carbon dioxide as the reactant,
• d) the reaction is conducted at temperatures of 20-150 ° C and the resulting from the dissolved carbon dioxide pressure to a metal oxide gel,
• e) the reaction mixture is aged with a metal oxide gel without moving the pressure vessel at the reaction temperature for at least 1 hour, preferably 8-12 hours, and then
• f) an airgel is prepared by extracting all components except the metal oxide gel from the reaction mixture of feature d) with a supercritical substance, and
• g) then at least one active compound is bound adsorptively from a supercritical gas to the resulting airgel.

there it is particularly advantageous if the supercritical substance is carbon dioxide is because of its supercritical Properties are particularly well known. Also is carbon dioxide non-toxic and therefore especially in the pharmaceutical sector or food sector good use.

Advantageous it is when at least one active ingredient is a pharmaceutically active Substance, a cosmetic substance and / or a color pigment. It is also advantageous if at least one active substance in the airgel in a spatial Structure is brought, which corresponds to that of a solvent.

In A further advantageous embodiment is as a metal alkoxide Tetramethyl or tetraethyl orthosilicate or alumium sec-butoxide used.

advantageous Reaction temperatures for the preparation are temperatures of 20-150 ° C, preferably 20-60 ° C, especially preferably 40 ° C.

The Task is also by use with the features of the claim 9 solved.

Advantageous is it when the drug carrier in the spatial Close to his Place of action is brought, the drug carrier then in a solvent disbanded is, whereby the at least one active ingredient is released in the solvent. The release of the at least one active ingredient takes place in controlled Kind of what an advantage over the solution of a Active substance in a fluid solvent is, because the latter has to be made of a molecule to solve.

With Advantage is the solvent an aqueous one solution with a pH in the range of 1-10 and / or pure water and / or an aqueous one Electrolyte solution.

A is particularly advantageous use for the drug carrier a drug delivery system in pharmacy.

One Process for the preparation of aerogels, attached to this Invention closer described, allows a particularly efficient production of a with at least one active substance loaded aerogels.

in the The following is the functional support according to the invention, its Production and its use described by way of example.

Aerogels are three-dimensional networks from which the solvent has been removed. They have densities of 0.003 to 0.8 g / cm ³ . Production and properties of aerogels are in principle z. B. from the US patents US 2093454 A and US 5395805 A wherein silica aerogels are prepared in a sol-gel process according to the following reaction scheme:

Of the Alcohol and the solvent become supercritical from the gel Conditions of the solvent used away.

Silica aerogels can be produced in both a hydrophilic and a hydrophobic form ( US 5409683 A ).

The fine, open-pore structure of aerogels allows their loading z. B. with carbon particles, as shown in the US 5587107 A is described. Here, organically modified silica aerogels are loaded with carbon particles by carrying out the pyrolysis of hydrocarbons at a high temperature (600-1300 ° C) in the presence of silica aerogels. The pores of the airgel are thereby loaded with the products of pyrolysis (carbon). According to the US 5855953 A this process will be extended to other substances. For example, the aerogels are loaded with Si, Fe, Ni, Ti, Cr and Li.

The literature describes the use of aerogels as adsorbents, e.g. B. for air purification. Both pure silica aerogels and organically modified aerogels come into question. S. Yoda et al. (J. Mater. Chem., 10, 2000, 2151) have used aerosols containing TiO ₂ to remove benzene from the air. The adsorption and photocatalytic decomposition of benzene on aerogels was investigated. Ahmed and Attia (Applied Thermal Engineering, 18, 1998, 787) have determined the adsorption of noxious gases, such as NO _x , CO, SO ₂ , on CaO and MgO-containing aerogels. It could be shown that the corresponding aerogels have high adsorption capacity.

From the DE 19719395 A1 is the use of organically modified silica aerogels (eg, according to the method of DE 4316540 A1 . WO 96/22942 A1 as adsorbent for the purification of liquids and gases as well as for the isolation of organic compounds from liquids. The method is based on the adsorption of organic substances such as chlorophenol, toluene, benzene, phenol, and the antibiotic cephalosporin from liquid and gaseous phases. Loads of up to 10% could be achieved. The authors aimed to isolate these substances in aerogels in order to improve the purification processes.

The use of aerogels in the pharmaceutical field has hitherto been limited to improving the flowability of powdered substances ( DE 19653758 A1 ).

Out It is thus only known to the prior art that the passive properties, such as B. the adsorption properties of the aerogels in air purification to use.

The use according to the invention uses aerogels so that a change the aerogels itself leads to the rapid release of active substances. there wear this Airgel itself to release the drug at.

This is based on a model concept based on the 1a - 1c is pictured.

In 1a is the solution of an active substance 1 in a solvent 10 shown. According to the Flory-Huggins model for liquids, take the molecules of the solvent 10 so-called cells 11 one. The molecule of the active substance 1 is larger than the molecules of the solvent 10 so the active ingredient 1 in this illustration, two cells 11 occupies.

In 1b In contrast, the inventive arrangement of the active ingredient 1 in an airgel 2 shown. The airgel 2 consists of a grid structure, eg. B. a SiO ₂ grid. Otherwise is in the airgel 2 contain only air, ie the analogue to the Flory-Huggins cell is empty.

Will now the airgel 2 with a solvent 10 brought into contact, the lattice structure decomposes very quickly; this is in 1c shown. The empty seats in the airgel 1 are now of molecules of the solvent 10 ingested.

The active substance 1 can thus with the airgel 2 get as drug carriers to its site and there released quickly when the airgel 2 with a solvent 10 comes into contact.

Fast effective and poorly water-soluble Active ingredients, the z. B. orally, can by their enclosure to targeted release of various parts of the organism. The transition into the bloodstream of the organism happens through the transition through the membrane cell wall. This transfer is in any case the faster, the higher the current local concentration is. This high concentration must be prepared extrapolated immediately, since the Active ingredient even in a flowing system, z. B. in the intestine, is. If the active ingredients z. B. crystalline used, there is a known, slow dissolution kinetics, which in the Usually only by the size of the crystals and their shape can be influenced. It is expected that Unabsorbed drug amounts are excreted or in places arrive at which they are not to be resorbed.

The Invention allows rapid release of active ingredients based on the principle that the active substance is based on an inert adsorptive carrier (adsorbent) in the spatially similar Arrangement is adsorbed, as he later in a solvent as solved Substance is present. For this it is necessary that the adsorptive carrier with the solvent a quick response goes to the goal, the spatial Destroy structure of the adsorbent. Very suitable are therefore very light adsorbents.

In a variant of the method for loading the airgel with a Active ingredient is this in a supercritical Gas solved and brought into contact with the airgel. The loading takes place Adsorption from the supercritical solution instead of.

The such loaded aerogels are used as carriers of the drug substances used. The release kinetics of the invention adsorbed Active substance in aqueous Media is faster than the same active ingredient of a crystalline Shape. The rapid release of the drug is poorly soluble and fast acting drugs very beneficial.

by virtue of the invention is procedural effort for the conditioning The crystals are avoided and it is at the same time a fast dissolution kinetics allows.

To be in an adsorptive carrier (Adsorbent) specifically produced such pores in which a molecular adsorbed drug in similar spatial Arrangement is present, as he would be present in a solvent. by virtue of The molecular structure of the active ingredient can be modified neither crystalline nor amorphous. A second necessary Step of the use according to the invention is the destruction the network of the adsorbent by the solvent at a rate the higher is as the, the z. B. by van der Waals forces to an agglomeration of the active ingredient leads. As a result, it is necessary that the adsorbent is not a large specific one Mass may possess, as it is the "wrapping process" of the active ingredient through the solvent otherwise disabled.

The Application of this principle is possible if an airgel is used as light adsorbent, its structure, as described in the literature, is easy to control.

exemplary were silica aerogels by adsorption from the supercritical solution loaded with active ingredients. Supercritical solvent have the advantage that they all in principle because of their very low viscosity accessible Reach pores. Furthermore, the built-up capillary pressure is compared small to liquids enough not to destroy the filigree pore structure.

The aerogels used according to the invention have very high internal surfaces of 500 to 800 m ² / g, determined by BET measurements by means of nitrogen adsorption. They usually have open pores. The aerogels can in principle be brought into any suitable form (powders, tablets, etc.).

to Loading with a drug is the finished airgel in a pressure vessel in Contact with the solution of the corresponding active ingredient in a suitable supercritical Gas brought. The pressure and the temperature of the process depend on the solubility of the corresponding active substance in the supercritical gas and of the chemical and thermal stability of the active ingredient.

After this the adsorption equilibrium is reached, residual gas is removed and the loaded airgel removed from the pressure vessel. The concentration of the active ingredient can be resolved by dissolution of the airgel in a suitable solvent (eg acetone, Acetonitrile, ethanol) and subsequent analysis by HPLC become.

Of the Advantage of this variant of the process is that after the Loading no removal of the solvent needed is, such. B. in the adsorption from the liquid phase, since the residual adsorption Of gases is usually tolerated while liquids for contamination to lead would.

The loaded aerogels were analyzed by X-ray spectroscopy. It has been shown that active substances in the aerogels are not in the crystalline form.

at in contact with aqueous solutions the aerogels disintegrate instantly. This is the active ingredient released in the manner described. The concentration of the released Stoffes and their dependence from time can z. B. measured using spectroscopic methods become.

In Several examples have been found that adsorbed on the airgel Active ingredient dissolves faster in water, or in 0.1 N HCl solution than the same active ingredient in the crystalline form.

The silica airgel acts as an inert active substance carrier. Silica aerogels consist to 99% of SiO ₂ , which is chemically inert and - in small quantities - harmless to health.

For the rest, can the active substance carrier according to the invention a carrier for one second active ingredient are coupled to the other release kinetics of the second active ingredient allowed. This can be z. B. also a crystalline Form of the second active ingredient, that of an airgel according to the invention is surrounded. In this case, the drug carrier according to the invention also loaded with the same active substance as the second active ingredient for one delayed Release is provided.

• – die Beladung des Adsorbens, das Wirkstoffträger und notwendiges Hilfsmittel ist, kann durch Prozessbedingungen wie Druck und Temperatur fein eingestellt werden;
• – aufwändige Mischprozesse zwischen großen Trägermengen und kleinsten Wirkstoffmengen entfallen;
• – Konditionierungsschritte, wie die Einstellung bestimmter Korngrößen entfallen;
• – Wirkstoffe aus dem erfindungsgemäßen Verfahren werden schneller freigesetzt als aus der kristallinen Form und liegen damit an der Zielstelle ihres Einsatzes in höchstmöglicher Konzentration vor.

In summary, the method according to the invention has the following advantages:

• - The loading of the adsorbent, the drug carrier and necessary tool, can be fine tuned by process conditions such as pressure and temperature;
• - Elaborate mixing processes between large volumes and smallest amounts of active ingredient omitted;
• - conditioning steps, such as the setting of certain grain sizes omitted;
• Active substances from the process according to the invention are released more rapidly than from the crystalline form and are therefore present at the target site of their use in the highest possible concentration.

Therefore can procedural steps saved in the manufacturing process be, in use as a drug carrier necessary amounts of active ingredient be lowered because the amount of excreted drug by the mentioned flow process is reduced.

The Invention will be additional hereinafter explained using examples. In this case, ketoprofen is used as the active ingredient. Basically but it is possible also other pharmaceutically active substances, cosmetic substances or to use colored pigments as the active ingredient. So can an airgel applied to the skin with a care substance in a grinding form be where the airgel is due to the naturally existing moisture or due to additional Moisturizing decomposes and thus the active ingredient quickly and in controlled Way free.

Example 1: Loading of a silica Airgel with ketoprofen (proof of loading capacity)

For this test airgel with the density 0.032 g / cm ³ and the inner surface 534 m ² / g was used. It was made according to the procedure outlined in the Annex.

there were 0.5 grams of the above airgel and 0.174 grams of ketoprofen as active ingredient a pressure vessel added. The volume of this pressure vessel is 248 ml.

Thereafter, 125.7 g of CO _{2 was} added at 70 ° C. The pressure was 150 bar. After 10 hours, the pressure was released. The airgel loaded with the active ingredient was removed from the pressure vessel, ground to powder and dispersed in 10 ml of acetonitrile. After 1 hour, the concentration of ketoprofen in acetonitrile was measured. The calculation showed the loading of 0.12 g ketoprofen / 1 g airgel. The corresponding loading isotherm is in 2 shown.

Example 2: Release of the ketoprofen from the airgel

For this Experiment was the loaded with ketoprofen airgel example 1 used.

One Part of the airgel was ground to powder.

• 1.) 0,0838 g Aerogel Pulver,
• 2.) 0,089 g Aerogel stückig
• 3.) 0,0098 g Ketoprofen kristallin

gegeben. Die insgesamt eingebrachte Wirkstoffmenge ist in allen 3 Beispielen gleich. Die augenblickliche Mischung wurde mittels eines mechanischen Blattrührers gewährleistet. Jedem Behälter wurde jede 5 min eine flüssige, feststofffreie Probe entnommen. Die Konzentration des Ketoprofens in diesen Proben wurde mittel eines UV Spektrometers gemessen.In three containers, each filled with 900 ml of 0.1 N HCl, was incubated at 37 ° C

• 1.) 0.0838 g of airgel powder,
• 2.) 0.089 g airgel lumpy
• 3.) 0.0098 g of ketoprofen crystalline

given. The total amount of active ingredient introduced is the same in all three examples. The instant mixture was ensured by means of a mechanical blade stirrer. Each container was sampled every 5 minutes with a liquid, solids-free sample. The concentration of ketoprofen in these samples was measured by means of a UV spectrometer.

The corresponding concentration curve is in 3 shown.

Result: even from lumpy Airgel, the drug is much faster than from the crystalline form released.

attachment

Method of acceleration the production of aerogels

Summary

The production of metal oxide aerogels has been significantly accelerated by the use of supercritical CO ₂ during the gelation process. Transparent silica aerogels with densities 0.003 <ρ <0.2 g / cm ³ were prepared in a 2-step process. In the first step, tetraalkylorthosilicate is partially hydrolyzed in a suitable solvent to give a sol. In a second step, the sol converts to a gel with the addition of supercritical CO ₂ . The achieved gelation times are faster by a factor of 10-200 than in the literature.

Method of acceleration the production of aerogels

The process described below relates to the preparation of metal oxide aerogels as described in (Droege et al., U.S. Patent 5,395,805 A. ) are defined.

Aerogels are three-dimensional networks from which the solvent has been removed. They have densities of 0.003 to 0.8 g / cm ³ . Metal oxide aerogels are produced in a sol-gel process. For "sol" and "gel" the terms defined in CJ Brinker, Sol-Gel-Science, Academic Press (1990) are used.

The first metal oxide aerogels were synthesized in 1930 by SS Kistler ( US Patent, 2249767A ) by extraction of water from silica gel and subsequent removal of the extractant under supercritical conditions. The aerogels with the density of 0.05 g / cm ³ and the porosity of 98% could be produced in his process within 3 weeks.

Teichner et al. ( US Patent, 3672883A ) have described a process that significantly accelerates the production of aerogels. In this process, tetraalkylorthosilicates (tetramethylorthosilicate (TMOS) or tetraethylorthosilicate (TEOS)) are mixed with 1 to 5 of the stoichiometric amount of water, with alcohol and corresponding catalyst (bases or acids) in one step. Hydrolysis of the tetraalkyl orthosilicate followed by condensation of the hydrolysis products gives a gel. This chemical reaction, a 1-step reaction, can be described by the following scheme:

The alcohol and the solvent are removed from the gel under supercritical conditions of the ver Used solvent removed. For this, the supercritical conditions of the solvent, ie high temperatures (200-300 ° C) and pressures (50-100 bar) are needed, which is disadvantageous.

An improvement by Tewari et al. ( US Patent, 4610863A ) (involves the extraction of the organic solvent with liquid CO _2. The CO ₂ is brought into the supercritical state after extraction.

• ρ_Ziel ist die Zieldichte des Gels,
• m_SiO₂ – die Masse von SiO₂ in dem entsprechenden Alkoxid,
• V_{Re ak tan den} – das Volumen der Reaktanden,
• V_{Lösungsmittel} – das Volumen des Lösungsmittels.

In a one-step process, crack-free silica aerogels with a density of 0.02 <ρ <0.3 g / cm ³ can be produced in various forms. The achievable density - the target density - is, inter alia, a function of the dilution of the reactants with the appropriate solvent. The required amount of solvent can be calculated for a target density approximately according to the following formula.

• ρ _target is the target density of the gel,
• m _SiO₂ - the mass of SiO ₂ in the corresponding alkoxide,
• V _{Re ak tan den} - the volume of reactants,
• V _solvent - the volume of the solvent.

The 1-step process is very time consuming. In addition, aerogels of density ρ <0.02 g / cm ³ can not be produced by this method.

The next step in improving the production of silica aerogels was made by the working group of the Lawrence Livermore National Laboratory. Tillotson et al. WO 92/03378 A1 . US Patent, 5275796A ) have described a 2-step process that allows the synthesis of the aerogels with densities between 0.003 g / cm ³ and 0.8 g / cm ³ . During the first step, tetraalkylorthosilicates (TMOS or TEOS) are mixed with an under-stoichiometric amount of water, alcohol, and catalyst (eg, HCl). Under these conditions, the reaction [1] takes place only partially. Tillotson distilled off the solvent and by-products (alcohol) from the resulting mixture. The remaining high-viscosity mixture (called "precondensed silica" by the authors) is diluted in the second step with a non-alcoholic solvent. After the addition of basic catalyst, a gel is formed which gives an airgel after supercritical drying.

In the 2-step process, the low-density aerogels (ρ <0.02 g / cm ³ ) can also be produced. A typical gelation time for such aerogels is over 72 hours. The process can also be used to prepare other metal oxide aerogels, the teachings of A-1 at different temperatures, however, is to be redetermined.

• – Für die Herstellung der Aerogelen niedriger Dichte wird eine lange Gelierungszeit benötigt. Die Katalysatoren (z. B. NH₄OH) können die Reaktion beschleunigen, sie beeinflussen aber die Porengrösse und Lichtdurchlässigkeit der Aerogele.
• – Nach dem ersten Schritt muss der Alkohol abdestilliert werden.

All these methods have the following disadvantages:

• - For the production of aerogels low density long gelation time is needed. The catalysts (eg NH ₄ OH) can accelerate the reaction, but they affect the pore size and translucency of the aerogels.
• - After the first step, the alcohol must be distilled off.

The The method described here avoids these disadvantages.

In the process, the gel is prepared in two steps. The first step corresponds to that of Tillotson et al. ( WO 92 / 03378A1 ). As an example of silica aerogels, TMOS is mixed with a substoichiometric amount of water, with methanol and HCl (1 mole TMOS: 2.4 moles methanol: 1.3 moles H ₂ O: 10 ^-5 moles HCl). The reaction takes about 30 minutes at room temperature.

To Sequence of the reaction is the mixture with a non-alcoholic solvent diluted (eg acetonitrile), until the desired Concentration of the mixture (and thereby the target density of the gel) is reached. The needed Acetonitrile amount can be calculated according to the formula (2). One Advantage of the process is that no distillation of alcohol carried out becomes.

Thereafter, enough water to reach the stoichiometric amount and the catalyst (NH ₄ OH) are added. The amount of catalyst can be estimated according to (1 mol TMOS: 10 ^-n mol NH ₄ OH, 1 <n <4). Generally, it is observed that at n near 4 a less transparent and with larger pores equipped (and thus disadvantageous) airgel is obtained. Immediately thereafter, the mixture is introduced into a pressure vessel and - for example for silica aerogels - to T ₁ = 20-150 ° C, preferably 40 ° C, heated.

A second advantage of the method is that it has surprisingly been found that the subsequent addition of CO ₂ at the same or different temperature T ₁ leads to a dramatic increase in the reaction rate. The amount of CO ₂ required and appropriate depends on the temperature, the target density and the type of gel and must be determined experimentally for each metal oxide gel. For silica aerogels at 40 ° C, the doctrine of A-1 to be used.

With the addition of CO ₂ , the viscosity of the solution increases (a physical solution alone would lead to a reduction in viscosity) and, after the in A-1 given ratio m _CO2 : m _{sol is} achieved, the gelation takes place. The achieved gelation times are faster by a factor of 10-200 than in the literature. The mode of action of CO ₂ is surprising since the use of other gases (eg nitrogen, freons) in the same process with or without acid does not lead to the reaction acceleration described in the process. Therefore, a simple theory, such as. As a catalytic effect of CO ₂ exclude.

The quality of the products produced by this process is very temperature dependent (T ₁ ). If CO _{2 is} supplied at 20 ° C, then obtained after drying opaque white aerogels. From 30 ° C, the aerogels become more transparent and 40 ° C was found to be the optimum temperature for silica aerogels (see Example 1). Gel produced at 40 ° C. gives the transparent airgel, whose transparency and pore size correspond to those of 2-step processes known from the literature. Higher temperatures are not preferred because no further acceleration of the reaction is observed, but the energy input is unnecessarily increased. The temperatures must be determined experimentally for each metal oxide airgel.

The amount of CO _{2 added also} influences the properties of the aerogels very strongly. Will that be in A-1 - example of silica aerogels - given appropriate ratio m _CO2 : m _sol exceeded, the aerogels are opaque and soft. Other properties such as pore size and density remain unchanged. If less CO _{2 is added} than the appropriate amount, gelation does not take place in the short time. The curve after A-1 must be determined experimentally for each metal oxide airgel according to the teaching of this patent.

After the gel has formed, the residual solvent is extracted with supercritical gas, for example with CO ₂ . The extraction time depends on the amount of gel and follows recommendations by Tewari et al. ( US Patent 4610863A ). After the solvent has been completely removed, the pressure vessel is so relaxed to 1 bar that a gas relaxation of 2-4 l / min based on 1 bar and 20 ° C is performed. Higher extraction rates cause cracks in the aerogels. Apart from CO ₂ , other substances with low critical temperatures and pressures (eg Freon 13, Freon 23, Freon TF) can be used for the extraction. Since CO _{2 has} already been introduced during gelation in the process described here, it is preferred to use this substance as an extraction agent. In addition, CO _{2 is} inexpensive and environmentally friendly. Aerogels with a density of 0.003 <ρ <0.2 g / cm ³ can be produced by the method described here. Since, in the production of aerogels of higher density, the gelation time is very short (10-60 min), even in the context of the abovementioned 1- and 2-step processes known from the literature, this process becomes less advantageous at high densities of aerogels.

The Advantages of the method are described in Example 1.

Example 1: Preparation of a silica airgel with a density of 0.02 g / cm ³

5.8 g of TMOS, 2.9 g of methanol, 0.66 g of water and 0.23 g of hydrochloric acid (0.006 mass%) were mixed for 30 minutes at room temperature. Thereafter, 80.2 g of acetonitrile, 0.52 g of water and 1.34 g of ammonia (1 Ma%) were added. All components were mixed for a further 2-3 minutes and the sol was immediately fed to a pressure vessel without alcohol distillation. The volume of the pressure vessel was 250 ml. The pressure vessel was heated to T ₁ = 40 ° C, during which it was pivoted. After 30 minutes, 64.2 g of CO _{2 were} fed in small portions (3-5 g each time) over 20 minutes. The visible gelation took place after 20 min. The gel was aged in the pressure vessel for 10 hours under the following conditions: 37 bar, 40 ° C.

Subsequently, the solvent was extracted with supercritical CO ₂ . The extraction conditions were: T = 40 ° C, P = 100 bar, CO ₂ volumetric flow 2-4 l / min, t _extraction = 14 hours.

The transparent airgel was obtained with the following properties:
BET surface area: 570 cm ² / g, average pore diameter: 18 nm.

The Effect of the added carbon dioxide is surprising. It can not be replaced by other combinations of gas and catalyst. To clarify the superiority of the described method, the following counter examples became experimental determined.

Counterexample 1: Replacement of CO ₂ by freon 23 and nitrogen

The Sol was prepared as in Example 1 and immediately afterwards pressure vessel fed. Freon 23 was added at room temperature. After 5 g Freon 23 is added was created in the pressure vessel a white one Rainfall. Further addition of the gas had within 5 hours no gelation. The same effect was also used observed by nitrogen.

Counterexample 2: Replacement of CO ₂ by a combination of a gas and an acid

The Sol was prepared as in Comparative Example 1. After it was fed to the pressure vessel, was additionally 5 g of a 0.1% HCl added. After each Freon 23 and nitrogen supplied. In both cases I got a white one Rainfall. Gelation did not occur within 5 hours.

Claims (16)

Active substance carrier with a hydrophilic metal oxide airgel or silica airgel produced by supercritical drying, characterized in that the spatial structure of the airgel ( 2 ) with at least one active substance ( 1 ), wherein the loading of the active substance by means of a supercritical gas in which the active substance ( 1 ) and wherein the spatial structure with water or an aqueous electrolyte solution as a solvent ( 10 ) for release at the site of action of at least one active substance ( 1 ) is destructible. Active substance carrier according to claim 1, characterized in that the airgel ( 2 ) has a bulk density in the range of 0.003 g / ml to 0.3 g / ml. Active substance carrier according to claim 1 or 2, characterized in that the airgel ( 2 ) has an inner surface area of at least 300 m ² / g. Active substance carrier according to at least one of the preceding claims, characterized in that the airgel ( 2 ) has a porosity of more than 90%. Active substance carrier according to at least one of the preceding claims, characterized in that the at least one active substance ( 1 ) has a pharmaceutically active substance, a cosmetic substance, a fragrance, a flavoring and / or a color pigment. excipient according to at least one of the preceding claims, characterized that a second active ingredient is provided, which with the first active ingredient may be identical and the delayed release of the second Active ingredient coupled with a second airgel as a drug carrier is and / or is in a form containing a sustained release the second active ingredient causes. excipient according to claim 6, characterized in that the second active ingredient in crystalline form. excipient according to at least one of the preceding claims, characterized a metal alkoxide used to prepare the metal oxide airgel Tetramethyl or tetraethyl orthosilicate or aluminum secbutoxide is. Use of the active ingredient carrier after at least one of the preceding claims for oral or dermal application. Use of the active ingredient carrier according to at least one of claims 1 to 8, characterized in that the active ingredient carrier is brought into the spatial proximity of its site of action, the active ingredient carrier in a solvent is dissolved, and the at least one active ingredient ( 1 ) in the solvent ( 10 ) is released. Use of the active ingredient carrier according to claim 10, characterized in that the solvent ( 10 ) Is water or an aqueous electrolyte solution having a pH in the range of 1-10. Process for the preparation of a drug carrier with a hydrophilic airgel, wherein the airgel ( 2 ) is dried at supercritical conditions and is loaded during drying and / or after drying by adsorption with at least one active ingredient within 0.1 to 20 hours, wherein a) a metal alkoxide with a substoichiometric amount of water and so much suitable solvent in that a liquid phase is formed, which is reacted with a catalyst, b) the mixture of a) subsequently with so much water that the stoichiometric amount is achieved, and enough suitable solvent is added to form a liquid phase and the target density is reached, c) the mixture of b) is fed to a pressure vessel and mixed with a suitable amount of carbon dioxide as a reactant, d) the reaction at temperatures of 20-150 ° C and the pressure resulting from the dissolved carbon dioxide to a Metal oxide gel is performed, e) the reaction mixture with a metal oxide gel without movement of the pressure vessel rs at the reaction temperature at least 1 hour, preferably 8-12 hours, is aged and then f) an airgel is prepared by all components except the metal oxide gel from the reaction mixture of e) are extracted with a supercritical substance and g) then at least one Active substance adsorptively bound from a supercritical gas to the resulting airgel. Method according to claim 12, characterized in that that the supercritical Substance is carbon dioxide. Method according to one of claims 12 or 13, characterized in that at least one active substance ( 1 ) has a pharmaceutically active substance, a cosmetic substance, a fragrance, a flavoring and / or a color pigment. Method according to at least one of claims 12 to 14, characterized in that the metal alkoxide tetramethyl or tetraethyl orthosilicate or aluminum sec-butoxide. Method according to at least one of claims 12 to 15, characterized in that the reaction at temperatures of 20-150 ° C, preferably 20-60 ° C, especially preferably 40 ° C, expires.