MXPA97006412A - Use of inorganic aerogels in the farmaceut industry - Google Patents

Abstract

The invention relates to the use of inorganic aerogels as auxiliary material and / or vehicle for active ingredients and / or pharmaceutical preparations.

Description

USE OF INORGANIC AERQGELS IN THE PHARMACEUTICAL INDUSTRY DESCRIPTIVE MEMORY This invention relates to the use of inorganic aerogels as auxiliaries and / or excipients for compounds and / or active pharmaceutical preparations. Aerogels, in particular those having porosities of more than 60% and densities below 0.6 g / cm 3, have an extremely low thermal conductivity and are therefore used as an insulating material to heat as described, for example, in EP-A-0 171 722. Moreover, the. use of aerogels for Cerenkov detectors based on their refractive index, which is very low for solids. In addition, thanks to the particular acoustic impedance of the aerogels, a possible use as a means of adaptation impedance is described in the literature, for example in the ultrasonic field. Aerogels in the broadest sense, that is, in the sense of "gel with air as a dispersant", are prepared by drying a suitable gel. The term "airgel" in this sense includes aerogels in the narrowest sense, xerogeneous and cryogenic. A dry gel is designated co or an airgel in the narrowest sense here if the gel liquid is removed to the greatest extent possible at temperatures above the critical temperature and starting from pressures above the critical pressure. However, if the gel liquid is removed subcitically, for example with the formation of a liquid / vapor limit phase, then the resulting gel is designated co or xerogel. When the term aerogels is used in the present application, it is aerogels in the broadest sense, that is, in the sense of "gel with air as a dispersant". In addition, aerogels can be subdivided basically into inorganic and organic aerogels. Inorganic aerogels have been known since 1931 (S.S. Kistler, Nature 1931, 127, 741). Since then, aerogels have been prepared to par + go of all kinds of starting materials. It was possible to prepare, for example, aerogels S1O2, AI2O3, T ?? 2 ZrÜ2, Sn? 2 L12O, Ce? 2 and V2O5, so Corno mixtures thereof (HD Gesser, PC Goswami, Chem. Rev. 1989, 89, 756 f). For some years, organic aerogels made from all kinds of starting materials have also been known, such as, for example, from rnelamma forrnaldehyde (RU Pekala, 3. Mater, Sci. 1989, 24, 3221 ). Aerogels can be prepared here in all kinds of different ways. For example,? 1O2 aerogels can be prepared by the acid hydrolysis and condensation of orthosilicate tetraethyl in ethanol. In this process, a gel is obtained which can be dried with the retention of the structure by means of surface drying. Preparation methods based on this drying technique are known, for example, from EP-A-0 396 076 or UO 92/03378. An alternative is offered as a procedure for the subcritical drying of S1O2 gels if they are reacted with a silylating agent containing chlorine before drying. The S1O2 gel can be obtained here, for example, by the acid hydrolysis of tet ralcoxysLlanos in a suitable organic solvent by means of water. After replacing the solvent with a suitable organic solvent, the gel obtained is reacted in an additional step with a silylating agent. The resulting S1O2 gel can be dried posteriorly in the air that comes from an organic solvent. In this way aerogels can be obtained with densities of less than 0.4 g / cm3 and porosities of 60% rnáe. The preparation process based on this drying technique is described in detail in UO 94/25149. The gels described above can be further treated with ralycoxysilane and be aged before being dried in the aqueous alcoholic solution to increase the network strength of the gel, e.g., as described in UO 92/20623. Moreover, the S1O2 gel can also be prepared on the basis of a water glass. The preparation process based on this technique is known from DE-A-43 42 548. German patent application 19502453.2 further describes the use of chlorine-free silliating agents. The aerogels obtained by supercritical drying are, depending on the procedure used specifically, hydrophilic or, in the short term, hydrophobic. In the long term, however, they are hydrophilic. This can be avoided by a hydrophobicizing step during suporcritical drying. Such a process is known from EP-A-0 396 076. Due to its preparation process, (silylated before drying), the dried aerogels are essentially hydrophobic. The use of colloidal silica in therapeutic copper compositions is known, for example, from US-A-4,123.51l. In the same way, the use of organic aerogels in medicine is known (UO 95/01165). It is an object of the present invention to search for novel applications for aerogels. It has now surprisingly been found that inorganic aerogels are suitable as an auxiliary and / or excipient for the active compounds and / or pharmaceutical preparations. It should be understood in the present invention that an inorganic airgel means an airgel that has been prepared based on inorganic materials. The term "aerogels based on inorganic materials" also includes in particular those aerogels that have been modified, for example by sil ila tion. Aerogels comprising mainly S1O2, AI2O3, TiO2, Zr2, or mixtures thereof are preferred.

Depending on the use they may have hydrophilic and / or hydrophobic surface groups (e.g., OH, OR, R). The preparation of aerogels having hydrophilic and / or hydrophobic surface groups can be carried out here by all methods known to the person skilled in the art, particularly aerogels containing hydrophilic and / or hydrophobic S1O2, in particular. The agents of 102. Moreover, it has been surprisingly discovered that by choosing a suitable hydrophilic and / or hydrophobic airgel, suitable substances can be released with which the airgel has been loaded in an accelerated or delayed manner. used as dispersants for dispersions of solid, liquid or gaseous substances in liquid or solid media, Moreover, hydrophilic and / or hydrophobic aerogels loaded with hydrophilic and / or hydrophobic substances can be incorporated without problems in hydrophilic and / or hydrophobic media, liquid , semi-solid or solid, in particular in order, with the help of aerogels hydrophilic, for introducing hydrophobic (ie, lipophilic) substances into liquid hydrophilic dispersion media and / or isolids, and with the aid of hydrophobic aerogels to introduce hydrophilic substances into liquid hydrophobic dispersion media. Hydrophobic aerogels, for example, float on hydrophilic aqueous media by means of which pharmaceutical excipient systems floating on the gastric juice are possible. In addition, it is also possible to convert hydrophilic or hydrophobic liquid substances into free flowing solid powders or granules. Problem-free processing, for example, giving tablets, capsules or suppositories is thus possible. In addition with suitable aerogels, it is also possible to prepare lotions, creams and gels with and without a peeling effect. Substances within the meaning of these applications are substances that can be used in the pharmaceutical industry, eg, pharmaceutical products, aromatic substances and flavors. The invention is described in greater detail in the following, with the help of working examples, if to be restricted by these.

EXAMPLES OF PREPORTION EXAMPLE 1 Preparation of a permanently hydrophobic 1% aerogel of a soda glass beaker solution (containing 7% by weight of SiO 2 and a Na 2: 2 ratio of 1: 3.3) was stirred together with 0.5 1 an acid ion exchange resin (styrene-divimlbenzene copolymer with sulfonic acid groups, available commercially under the name RDuolite C20), until the pH of the aqueous solution was 2.3. The ion exchange resin was subsequently removed by filtration and the aqueous solution was adjusted to a pH of 5.0 using a 1 molar solution of NaOH. The resulting gel was subsequently aged at 85 ° C for 3 more hours and the water was subsequently replaced by acetone using 3 1 of acetone. The gel containing acetone was subsequently silylated with tp ethiichlorosilane (5% by weight of tprnethylchlorosilane per gram of wet gel). The gel was dried in air (3 hours at 40 ° C, then 2 hours at 50 ° C and 12 hours at 150 ° C). The transparent airgel thus obtained had a density of 0.15 g / cm3, its specific surface according to BET was 480 rn2 / g and was permanently hydrophobic.

EXAMPLE 2 Preparation of a hydrophilic airgel The permanently hydrophobic airgel prepared in example 1 was pyrolyzed for 1 hour at 600 ° C in a gentle stream of air by means of a tube furnace. The transparent airgel obtained had a density of 0.18 g / cm 3, a specific surface area according to BET of 450 m2 / g and was hydrophilic.

EXAMPLES OF USE In the use examples, hydrophilic and hydrophobic aerogels such as those obtained according to the preparation examples 1 and 2 are used.

EXAMPLE 1 Humidity of aerogels Ae og l Hydrophobic Hydrophilic Acetone + + Ethanol + + Ethyl acetate + + n-Hexane + + Methanol + + i-Propanol + + Water + +: humectant; -: no humectant EXAMPLE 2 Water absorption of aerogeleß during intensive mechanical incorporation Water absorption (%) Description Hydrophilic airgel up to 240 free flowing powder 280 gelatinous consistency 300 highly liquid suspension Hydrophobic airgel up to 140 free flowing powder 260 viscous paste 320 suspension bl nca vi scosa EXAMPLE 3 Loading of aerogels with carboxyfluorescein of Na 5 g of airgel are treated with 50 ml of a solution of carboxyfluorescein of ethanolic Na of 1.5% strength and the mixture is stirred for 2 hours. After filtration, the residue is dried at room temperature under normal pressure and the product is sieved. A free-flowing powder is obtained.

Content of carboxyfluorescein of Na Hydrophilic airgel 6.2% Hydrophobic airgel 5.7% í.e. at least 38% of the amount of substance added is absorbed.

EXAMPLE 4 Release of Na carboxyfluorescein by aerogels Release device: Palette (USP) Medium: Water, 37 ° C Release time (rnin) 5 60 150 Hydrophilic airgel 51% 80% n.d Aerobic hi rofóbico 13 18% 38% EXAMPLE 5 Loading of aerogels with active pharmaceutical compounds Loading by suspension of the excipient (hydrophilic / hydrophobic airgel) in an active compound solution and the subsequent drying (normal pressure or reduced pressure) or the application of an active compound solution to the dry excipient and the subsequent subsequent drying. You get free flowing powder. A) Initially introduce 1 g of airgel, add 20 ml of a fluoroose ida solution of 5% strength (acetone) with stirring, allow the solvent to evaporate under normal pressure and at room temperature. Loading of active compound: 50% B) Initially introduce 1 g of airgel, add 2 ml of a fluoroose ida solution of 5% strength (acetone) with stirring, allow the solvent to evaporate under normal pressure and at room temperature repeat until the desired load (eg, four times) Active compound loading: 33.3% C) Impartially introduce 1 g of airgel, add a fluoroseride solution of 5% strength (acetone) to obtain a powder still flowable, drying later (normal pressure or reduced pressure) Active compound loading: 13.0% D) Initially introduce 1 g of airgel, add 15 rnl of a solution of fluorosemide-sodium of 1.3% strength (acetone) with agitation, allow the solvent to evaporate at normal pressure and at room temperature Active compound loading: 33.3% E) Initially introduce 1 g of airgel, add 15 i of a solution of penbutulol hernisulfate of 1.3% strength (ethanol / ethanol 1: 1) with agit ation, allow the solvent to evaporate at normal pressure and at room temperature Active compound load: 16.6% F) Initially introduce 1 g of airgel, add 20 ml of a solution of HOE 277 * of 1% strength (ethanol) with stirring , allow the solvent to evaporate at normal pressure and at room temperature 1? Loading of active compound: 16.6% * N, N- (3-rnetox? Pro? L) acid arc p? R? D? No-2,4-d? CarhoxLl ico (described in EP-A-0 409 119). G) Introduce micivalent 1 g of airgel, add 13.5 ml of a methylprednisolone solution of 0.7r > % Resistance (ethanol) with stirring, allow the solvent to evaporate at normal pressure and at room temperature Active compound loading: 9.1% EXAMPLE 6 Release of active pharmaceutical compounds from aerogels A) Release of netilprednisolone from hydrophobic airgel Loading: 9.1% methylprednisolone Release method: blade agitator method GP10 Medium: hydrochloric acid at 0.1 N Time (min) Release of substance Release of pure prednisolone (%) prednisolone from hydrophobic airgel (%) 15 18.8 16.8 120 84.1 41.1 480 91.5 58.7 1440 92.3 77.2 B) Release of rnetilprednisolone from aerogels Load: 9.1% methylprednisolone Release method: GP10 blade agitator method Medium: pH 7.5 phosphate buffer Time (min) Liberation Release Release of pure substance methylprednisomet ilpredni- (%) canvas from solon to airgel par-t r hydrophilic airgel hi- (%) drofo ico (%) 3 3.9 56.5 1.6 6 12.5 68.2 3.1 15 33.2 75.3 6.5 30 53.9 78.6 11.6 C) Release of Hoe 277 from aerogels Loading: 16.6% Hoe 277 Release method: GP10 blade agitator method Medium: hydrochloric acid at 0.1 N Time (rnin) Release of Hoe 277 Liberac: in from from airgel Hoe 277 to hydrophilic (%) pa rt Lr * ele a ro * hydrophobic gel (%) 6 94.3 20 .8 15 94.3 24 .9 30 94.8 28.9 D) Release of furosemide from aerogels Loading: 50% furosemide Release method: agitator method blade GP10 Medium: water Time (in) Release of substance Release of pure furose ida (%) furosemide to part of hydrophilic airgel (%) 3 8.7 2.3 OE¡ 6 15.7 2.7 15 29.9 5.5 30 49.5 9.0 EXAMPLE 7 Preparation of airgel tablets Recipe: Microcrystalline cellulose 1 part Corn starch 1 part Mg stearate 0.01 parts Aerogé1 * 0.05 parts *: Aerogels containing carboxyfluorescein of Na of Example 3 (hydrophilic or hydrophobic) Procedure: mixing of the components and subsequent direct tapping using an eccentric tablet press to give round biplane tablets (0 6 mm) with a mass of 100 mg and a radial compression resistance of 50 and 100 N. Tablets can be prepared without problems using hydrophilic and hydrophobic aerogels EXAMPLE 8 Preparation of airgel capsules Recipe: Airgel 2 parts Lactose 1 H2O D 80 ** 98 parts *: Aerogelee containing carboxifluoreecein of Na from example 3 (hydrophilic or hydrophobic) **: Meggle, Uasserburg Procedure: manual filling Free-flowing powders are obtained with both hydrophilic aerogels as with hydrophobic, which can be filled in capsules without problems.

EXAMPLE 9 (a, b, c and d) Preparation of hydrophilic or hydrophobic airgel suppositories Recipe: Airgel * 2 parts Lactose I H2O D 8O ** 98 parts *: Aerogels containing carboxyfluorescein of Na from example 3 (hydrophilic (a, b) or hydrophobic (c, d) **: Uitepsol H 12 (a, c ) or Uitepsol U 45 (b, d), HÜls, AG, Uitten Procedure: melt molding process Hydrophilic and hydrophobic aerogels can be easily incorporated into the two suppository bases.

EXAMPLE 10 (a, b, c and d) Preparation of airgel suppositories containing water Recipe: Airgel * 1 part Sol. Fluorescein sodium 1.5% strength 1 part Uitepsol ** 98 parts *: Aerogels (hydrophilic (a, b) or hydrophobic (c, d) **: Uitepsol H 12 (a, c) or Uitepsol U 45 (b, d), Hüls, AG, Uitten Procedure: molding procedure Fusion The aqueous phase can be incorporated without problems into the two suppository bases.

EXAMPLE 11 Preparation of an airgel lotion Recipe: Airgel 4.41 g Propylene Glycol 8.82 g Polysorbate 60 4.41 g Polysorbate 65 4.41 g Liquid paraffin, highly liquid 13.24 g Polyacrylic acid 0.22 g Solution at 1 N of sodium hydroxide 0.88 g Edetic acid, tetrasodium salt dihydrate 0.09 g Methyl 4-hydroxybenzoate 0.10 g Propyl -Hydroxybenzoate 0.01 g Water 63.41 g Both with the hydrophilic and hydrophobic airgel a white homogenous milk is obtained with a peeling effect.

EXAMPLE 12 (a and b) Preparation of gels containing airgel Recipe: Airgel * i1.0 g Miglylol 812 99.0 g *: Aerogels (hydrophilic) (a) or hydrophobic (b) Clear or slightly opalescent gels are obtained with a peeling effect.

EXAMPLE 13 Loading of hydrophilic or hydrophobic airgel with lipophilic substances Recipe: Oerogel * 3 g Sudan Red 0.5 g Isopropanol 80 g Sudan red is dissolved in isopropanol and stirred with the appropriate airgel for 2 hours. After separating the excess, liquid phase, the airgel is dried at room temperature and normal pressure. A free-flowing powder containing Sudan red is obtained.

A) Hydrophilic airgel with Sudan red 1 part Water 99 parts A homogeneous red suspension is obtained. The agglomeration of particles is not observed.

B) (Comparison example) Sudan red 0.1 parts Water 99 parts Even after intense agitation, the dispersal or dispersion of Sudan red in water does not take place. The product agglomerates strongly.

O Hydrophobic airgel with Sudan red 1 part Water 99 parts A homogeneous dispersion of the airgel containing Sudan red on the surface of the water is obtained without the occurrence of agglomerates.

EXAMPLE 15 Loading of airgel with hydrophilic substances hydrophobic hydrophilic Recipe: Airgel 1 part 1 part Water 1.4 parts 2 parts Water content (%) 58 66 IDafter intensive crushing, a homogenous free-flowing powder is obtained.

EXAMPLE 16? > Dispersion of hydrophilic substances in hydrophobic media A) Airgel (containing water) 1 part (hydrophilic or hydrophobic) 0 Sesame oil 50 parts A homogeneous suspension containing water with gentle agitation is obtained. Water separation can not be observed even after 24 hours.

B) Water 0.1 part Sesame oil 50 parts Even with vigorous agitation, the homogeneous dispersion of. water (hydrophilic model substance) in sesame oil is not possible. After a short time, droplets of water or dispersed are added. There is always a clear phase separation.

EXAMPLE 17 Preparation of hydrophilic airgel suppositories with a hydrophilic phase 5 included Recipe: Hydrophilic airgel 1 part Sol. of fluorescein of Na 2 pairs of 1.5% of resistance After the crushing, a powder of free flow is obtained that can be incorporated until a proportion of 33% (= 22% of hydrophilic phase) without problems and homogeneously in bases for suppository melted (Uitepsol H 12 or U 45). No hydrophilic phase of the suppositories escapes. The suppositories of Uitepsol H 12 with 5% sodium fluorescein solution (1.5% strength) are, however, homogeneous. The hydrophilic phase escapes suppositories.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - EJ use of modified surface inorganic aerogels as an auxiliary and / or excipient for active pharmaceutical compounds and / or compositions.

2. The use according to claim 1, wherein the modified surface aerogels have hydrophobic surface groups,

3. The use of aerogels according to claim 1 or 2 as pharmaceutical auxiliaries for solid oral preparations, semi-solid and / or liquid.

4. The use of aerogels according to claim 1 or 2 as pharmaceutical auxiliaries for topical preparations.

5. The use of aerogels according to claim 4 for preparations for dermal, vaginal, rectal and oral administration.

6. The use of aerogels according to claim 1 or 2 as a pharmaceutical excipient for the accelerated, controlled and / or delayed release of pharmaceutical products.

7. The use of aerogels according to claim 6 for pharmaceutical forms that float in the gastric juice.

8. The use of aerogels according to claim 6 or 7 for the processing of liquid pharmaceutical products.

9. The use of aerogels according to at least one of the preceding claims, which comprises using airgel particles having porosities of more than 60% and densities of less than 0.6 g / cm3.