AU751582B2 - Use of inorganic aerogels in pharmacy - Google Patents

Description

Our Ref:7463464 P/00/OII Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT

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14oerhbt A±tiengesellschft 9-59k F'7IZ& k i. Act! ;wrwrw Brtmingstrasse 50CokI k4CVI QeFmny I&.7 Corncot~d Rloci' Kcsjchurett 0g 2 Uned s4mirs ej iwt DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Use of inorganic aerogels in pharmacy The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 Description Use of inorganic aerogels in pharmacy The invention relates to the use of inorganic aerogels as an auxiliary and/or excipient for pharmaceutical active compounds and/or preparations.

Aerogels, in particular those having porosities of over 60% and densities of under 0.6 g/cm 3 have an extremely low thermal conductivity and are therefore used as a heat-insulating material as described, for example, in EP-A-0 171 722. Moreover, the use of aerogels for Cerenkov detectors on the basis of their refractive index, which is very low for solids, is known.

Furthermore, on account of the particular acoustic impedance of the aerogels a possible use as matching impedance means, for example in the ultrasonic field, is described in the literature.

Aerogels in the wider sense, i.e. in the sense of "gel with air as a dispersant", are prepared by drying a suitable gel. The term "aerogel" in this sense includes aerogels in the narrower sense, xerogels and cryogels.

A dried gel is designated as an aerogel in the narrower sense here if the liquid of the gel is removed to the greatest possible extent at temperatures above the critical temperature and starting from pressures above the critical pressure. If the liquid of the gel, however, is removed subcritically, for example with formation of a liquid/vapor boundary phase, then the resulting gel is designated as a xerogel.

When using the term aerogels in the present 35 application, we are dealing with aerogels in the wider sense, i.e. in the sense of "gel with air as a dispersant".

2 Moreover, the aerogels can be basically subdivided 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 from all sorts of starting materials. It was possible here to prepare, for example, SiO 2 A1 2 0 3 TiO 2 ZrO 2 SnO2, Li20, CeO 2 and V 2 0 aerogels, and mixtures of these Gesser, P.C.

Goswami, Chem. Rev. 1989, 89, 756 ff). For some years, organic aerogels made of all sorts of starting materials, such as, for example, from melamine formaldehyde, have also been known Pekala, J.

Mater, Sci. 1989, 24, 3221).

Inorganic aerogels can be prepared here in all sorts -of different ways.

For example SiO 2 aerogels can be prepared by acidic hydrolysis and condensation of tetraethyl orthosilicate in ethanol. In this process a gel results which can be dried with retention of the structure by supercritical drying. Preparation processes based on this drying technique are known, for example, from EP-A-0 396 076 or WO 92/03378.

An alternative is offered by a process for the subcritical drying of SiO 2 gels if these are reacted with a chlorine-containing silylating agent before drying. The SiO 2 gel can be obtained here, for example, S 30 by acidic hydrolysis of tetraalkoxysilanes in a suitable organic solvent by means of water. After replacement of the solvent by a suitable organic oo solvent, the gel obtained is reacted in a further step with a silylating agent. The SiO 2 gel resulting here can then be dried in the air from an organic solvent.

Aerogels with densities of under 0.4 g/cm 3 and porosities of over 60% can thus be achieved.

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3 The preparation process based on this drying technique is described in detail in WO 94/25149.

The gels described above can moreover be treated with tetraalkoxysilanes and aged before drying in the alcoholic-aqueous solution in order to increase the gel network strength, e.g. as disclosed in WO 92/20623.

Furthermore, the SiO 2 gel can also be prepared on the basis of waterglass. The preparation process based on this technique is known from DE-A-43 42 548.

German patent application 19502453.2 moreover describes the use of chlorine-free silylating agents.

The aerogels obtained by supercritical drying are, depending on the process specifically used, hydrophilic or, in the short term, hydrophobic. In the long-term, however, they are hydrophilic.

This can be avoided by a hydrophobization step during the supercritical drying. Such a process is known from EP-A-0 396 076.

Due to their preparation process (silylation before drying), subcritically dried aerogels are permanently hydrophobic.

The use of colloidal silica in therapeutic copper com- 30 positions is known, for example, from US-A-4,123,511.

The use of organic aerogels in medicine is likewise known (WO 95/01165).

It was an object of the present invention to search for novel applications for aerogels.

-A/V It has now surprisingly been found that inorganic aerogels surface-modified r3 via silylation are suitable as an auxiliary and/or excipient 4 for pharmaceutical active compounds and/or preparations.

An inorganic aerogel is to be understood in the present application as meaning an aerogel which was prepared based on inorganic materials.

The term "aerogels based on inorganic materials" in particular also includes those aerogels which have been modified, for example, by silylation.

Aerogels mainly comprising SiO 2 A1 2 0 3 TiO 2 ZrO 2 or mixtures thereof are preferred. Depending on use, these can have hydrophilic and/or hydrophobic surface groups OH, OR, The preparation of aerogels having hydrophilic and/or hydrophobic surface groups can be carried out here by all processes known to the person skilled in the art. Hydrophilic or hydrophobic SiO 2 containing aerogels, in particular SiO 2 aerogels, are particularly preferred.

Moreover, it has surprisingly been found that by the choice of a suitable hydrophilic or hydrophobic aerogel appropriate substances with which the aerogel has been 25 loaded can be released in accelerated or delayed form.

Furthermore, aerogels can be employed as dispersants for dispersions of solid, liquid or gaseous substances in solid or liquid media. Moreover, hydrophilic or hydrophobic aerogels loaded with hydrophilic and/or 30 hydrophobic substances can be incorporated without problems in hydrophilic and/or hydrophobic, liquid, semisolid or solid media, in particular in order, with the aid of hydrophilic aerogels, to introduce hydrophobic lipophilic) substances into liquid and/or semisolid hydrophilic dispersion media, 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 5 excipient systems which float on gastric juice are possible. Furthermore, it is also possible to convert liquid, hydrophilic or hydrophobic substances into solid, freely flowable powders or granules. Problemfree processing, for example to give tablets, capsules or suppositories, is thus possible. Furthermore, with appropriate aerogels the preparation of lotions, creams and gels with and without a peeling effect is also possible. Substances within the meaning of these applications are substances which can be used in pharmacy, e.g. pharmaceuticals, aromatic substances and flavorings.

The invention is described in greater detail in the following with the aid of working examples, without being restricted thereby.

Preparation Examples Example 1 Preparation of a permanently hydrophobic aerogel 1 1 of a soda waterglass solution (with a content of 7% by weight of SiO 2 and an Na20:SiO 2 ratio of 1:3.3) was stirred together with 0.5 1 of an acidic ion-exchange resin (styrene-divinylbenzene copolymer having sulfonic acid groups, commercially available under the name Duolite C20), until the pH of the aqueous solution was 2.3. The ion-exchange resin was then filtered off and 30 the aqueous solution was adjusted to a pH of 5.0 using 1 molar NaOH solution. The resulting gel was then aged at 85 0 C for a further 3 hours and the water was subsequently replaced by acetone using 3 1 of acetone.

The acetone-containing gel was then silylated with trimethylchlorosilane by weight of trimethylchlorosilane per gram of wet gel). The gel was dried in air (3 hours at 40 0 C, then 2 hours at 50°C and 12 hours at 150"C).

6 The transparent aerogel thus obtained had a density of 0.15 g/cm 3 its specific surface according to BET was 480 m 2 /g and it was permanently hydrophobic.

Example 2 Preparation of a hydrophilic aerogel The permanently hydrophobic aerogel prepared in Example 1 was pyrolyzed for 1 hour at 600 0 C in a gentle stream of air by means of a tube furnace. The transparent aerogel obtained had a density of 0.18 g/cm 3 a specific surface area according to BET of 450 m 2 and was hydrophilic.

Use Examples: In the use examples, hydrophilic and hydrophobic aerogels are employed such as were obtained according to Preparation Examples 1 and 2.

Example 1: Wettability of aerogels: 9 9 4..

4* Aerogel Acetone Ethanol Ethyl acetate n-Hexane Methanol i-Propanol Water Hydrophilic Hydrophobic wetting; no wetting 7 Example 2: Water absorption of aerogels during intensive mechanical incorporation Water absorption Description Aerogel, hydrophilic up to 240 free-flowing powder 280 gelatinous consistency 300 highly liquid suspension Aerogel, hydrophobic up to 140 free-flowing powder 260 viscous paste 320 viscous white suspension Example 3: Loading of aerogels with Na carboxyfluorescein: 5 g of aerogel are treated with 50 ml of a strength ethanolic Na carboxyfluorescein solution 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 Na carboxyfluoroscein Aerogel, hydrophilic 6.2% Aerogel, hydrophobic 5.7% i.e. at least 38% of the amount of substance added is absorbed.

Example 4: Release of Na carboxyfluoroscein from aerogels: Release apparatus: Paddle (USP) 25 Medium: Water, 37°C Release Time (min) 5 60 150 Aerogel, hydrophilic 51% 80% n.d.

Aerogel, hydrophobic 13% 18% 38% 8 Example Loading of aerogels with pharmaceutical active compounds Loading by suspending the excipient (aerogel, hydrophilic/hydrophobic) in an active compound solution and subsequent drying (normal pressure or reduced pressure) or application of an active compound solution to the dry excipient and subsequent afterdrying. A free-flowing powder is obtained.

A) Initially introduce 1 g of aerogel, add 20 ml of a strength furosemide solution (acetone) with stirring, allow solvent to evaporate under normal pressure and at room temperature Active compound loading: B) Initially introduce 1 g of aerogel, add 2 ml of a strength furosemide solution (acetone) with stirring, allow solvent to evaporate under normal pressure and at room temperature, repeat up to the desired loading 4 times) Active compound loading: 33.3% 25 C) Initially introduce 1 g of aerogel, addition of a 5% furosemide solution (acetone) until a just still flowable powder results, afterdrying (normal pressure or reduced pressure) Active compound loading: 13.0% D) Initially introduce 1 g of aerogel, add 15 ml of a 1.3% strength furosemide-sodium solution (acetone) with stirring, allow solvent to evaporate at normal pressure and at room temperature 35 Active compound loading: 16.6% E) Initially introduce 1 g of aerogel, add 15 ml of a 1.3% strength penbutulol hemisulfate solution (methanol/ethanol 1:1) with stirring, allow 9 solvent to evaporate at normal pressure and at room temperature Active compound loading: 16.6% F) Initially introduce 1 g of aerogel, add 20 ml of a 1% strength HOE 277* solution (ethanol) with stirring, allow solvent to evaporate at normal pressure and at room temperature Active compound loading: 16.6% 'Pyridine-2, 4-dicarboxylic acid N,N,-(3-methoxypropyl)amide (described in EP-A-0 409 119) G) Initially introduce 1 g of aerogel, add 13.5 ml of a 0.75% strength methylprednisolone solution (ethanol) with stirring, allow solvent to evaporate at normal pressure and at room temperature Active compound loading: 9.1% Example 6 Release aerogels pharmaceutical active compounds from

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A) Release of methylprednisolone from hydrophobic aerogel Loading: Release method: Medium: 9.1% methylprednisolone Blade stirrer method GP Hydrochloric acid 0.1 N Time (min) 120 480 1440 Release of methylprednisolone pure substance 18.8 84.1 91.5 92.3 Release of methylprednisolone from hydrophobic aerogel 16.8 41.1 58.7 77.2 10 B) Release of methylprednisolone from aerogels Loading: Release method: Medium: Time (min) 3 6 Release of methylprednisolone pure substance 3.9 12.5 33.2 53.9 9.1% methylprednisolone Blade stirrer method GP Phosphate buffer pH Release of Release of methylprednisolone methylpednisolone from hydrophilic from hydrophobic aerogel aerogel 56.5 1.6 68.2 3.1 75.3 78.6 11.6 C) Release of Hoe 277 from aerogels Loading: Release method: Medium: 16.6% Hoe 277 Blade stirrer method GP Hydrochloric acid 0.1 N 9 9 .9 0 Time (min) 6 30 Release of Hoe 277 from hydrophilic aerogel 94.3 94.3 94.8 Release of Hoe 277 from hydrophobic aerogel 20.8 24.9 28.9 15 D) Release of furosemide from aerogels Loading: Release method: Medium: 50% furosemide Blade stirrer method GP Water Time (min) Release of furosemide pure substance Release of furosemide from hydrophobic aerogel 8.7 15.7 29.9 2.3 2.7 11 49.5 Example 7: Preparation of aerogel tablets: Recipe: Microcryst. cellulose 1 part Corn starch 1 part Mg stearate 0.01 parts Aerogel* 0.05 parts Na carboxyfluorescein-containing aerogels from Ex. 3 (hydrophilic or hydrophobic) Process: Mixing of the components and subsequent direct tableting using an eccentric tablet press to give round, biplanar tablets (0 6 mm) having a mass of 100 mg and a radial compressive strength of 50 and 100 N.

Tablets can be prepared without problems using both hydrophilic and hydrophobic aerogels.

Example 8: Preparation of aerogel capsules: Recipe: Aerogel* 2 parts Lactose 1 H20 D 80** 98 parts 20 Na carboxyfluorescein-containing aerogels from Ex. 3 (hydrophilic or hydrophobic) Meggle, Wasserburg Process: manual filling 25 Both with hydrophilic and with hydrophobic aerogels, free-flowing powders are obtained which can be filled into capsules without problems.

Example 9 b, c and d): Preparation of hydrophilic or hydrophobic aerogel suppositories: 12 Recipe: Aerogel* Witepsol** 2 parts 98 parts Na carboxyfluorescein-containing aerogels from Ex. 3 (hydrophilic b) or hydrophobic d)) Witepsol H 12 c) or Witepsol W 45 HUls AG, Witten Process: fusion molding process The hydrophilic and hydrophobic aerogels incorporated without difficulties into suppository bases.

can be the two Example 10 b, c and d): Preparation of water-containing aerogel suppositories: Recipe: Aerogel* 1 part Fluorescein sodium soln. 1.5% strength 1 part Witepsol** 98 parts Aerogels (hydrophilic b) or hydrophobic d)) Witepsol H 12 c) or Witepsol W 45 Hols 20 AG, Witten Process: fusion molding process The aqueous phase can be incorporated difficulties into the two suppository bases.

without 13 Example 11: Preparation of an aerogel lotion: Recipe: Aerogel 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 Sodium hydroxide solution 1 N 0.88 g Editic acid, tetrasodium salt dihydrate 0.09 g Methyl 4-hydroxybenzoate 0.10 g Propyl 4-hydroxybenzoate 0.01 g Water 63.41 g Both with the hydrophilic and with the hydrophobic aerogel, a white homogeneous milk with a peeling effect results.

Example 12 (a and b): Preparation of aerogel-containing gels Recipe: Aerogel* 11.0 g Miglyol 812 99.0 g Aerogels (hydrophilic) or hydrophobic 15 Clear or slightly opalescent gels with a peeling effect result.

Example 13: Loading of hydrophilic or hydrophobic aerogel with lipophilic substances Recipe: Aerogel 3 g Sudan Red 0.5 g Isopropanol 80 g 14 Sudan Red is dissolved in isopropanol and stirred with the appropriate aerogel for 2 hours. After separating off the excess, liquid phase, the aerogel is dried at room temperature and normal pressure. A free-flowing Sudan Red-containing powder is obtained.

Example 14: Dispersion of lipophilic substances in hydrophilic media A) Aerogel, hydrophilic with Sudan Red Water 1 part 99 parts A homogeneous red suspension is obtained. Agglomeration of particles is not observed.

B) (Comparison example) Sudan Red Water 0.1 parts 99 parts 9.

9 4* 9 9* 9 Even after intensive shaking no wetting or dispersion of Sudan Red in water takes place. The product agglomerates strongly.

25 C) Aerogel, hydrophobic with Sudan Red Water 1 part 99 parts A homogeneous dispersion of the Sudan Red-containing aerogel on the surface of the water is obtained without agglomerates occurring.

Example Loading of aerogel with hydrophilic substances Recipe Aerogel Water Water content hydrophobic 1 part 1.4 parts 58 hydrophilic 1 part 2 parts 66 15 After intensive trituration, a homogeneous free-flowing powder is obtained.

Example 16: Dispersion of hydrophilic substances in hydrophobic media A) Aerogel (water-containing) 1 part (hydrophilic or hydrophobic) Sesame oil 50 parts A homogeneous, water-containing suspension is obtained with gentle stirring. Separation of water cannot be observed even after 24 hours.

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

*e* 25 Example 17: Preparation of hydrophilic aerogel suppositories with o c an included hydrophilic phase Recipe: Aerogel, hydrophilic 1 part Fluorescein Na soln. 1.5% strength 2 parts After trituration, a free-flowing powder is obtained which can be incorporated up to a proportion of 33% 22% of hydrophilic phase) without problems and homogeneously in molten suppository bases (Witepsol H 12 or W 45) No hydrophilic phase escapes from the suppositories. Witepsol H 12 suppositories with sodium fluorescein solution strength) however, are inhomogeneous. The hydrophilic phase escapes from the suppositories.

P:\WPDOCS\CAB\SPECI7463464.doc-2/3/02 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers or steps but not the exclusion of any other integer or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in Australia.

PAN

Claims (8)

1. The use of inorganic aeroeels surface-modified via silvlation as an auxiliary and/or excipient for pharmaceutical active compounds and/or preparations.

2. The use as claimed in claim 1, wherein the surface-modified aerogels have hydrophobic surface groups.

3. The use of aerogels as claimed in claim 1 or 2 as a pharmaceutical auxiliary for solid, semisolid and/or liquid oral preparations.

4. The use of aerogels as claimed in claim 1 or 2 as a pharmaceutical auxiliary for topical preparations. The use of aerogels as claimed in claim 4 for preparations for dermal, vaginal, rectal and oromucosal administration.

6. The use of aerogels as claimed in claim 1 or 2 as a pharmaceutical excipient for the accelerated, controlled and/or delayed release of pharma- ceuticals. •o 7. The use of aerogels as claimed in claim 6 for pharmaceutical forms which float on gastric juice.

8. The use of aerogels as claimed in claim 6 or 7 for the processing of liquid pharmaceuticals.

9. The use of aerogels as claimed in at least one of the preceding claims, which comprises employing aerogel particles having porosities of over FpA and densities of under 0.6 g/cm 3 P:NWPDOCSkCAB\SPECI\7463464.de-2/3/2

17- Uses of inorganic aerogels surface-modified via silylation, substantially as hereinbefore described with reference to the Examples. DATED this 2 5 th day of March 2002. CABOT CORPORATION By Its Patent Attorneys DAVIES COLLISON CAVE *09* SS @0 S* S S S 55 @0 0 OS@ S 00 S *5bS *0 S 0 0655 *500 SOS. S .5.5 5 S 0 9