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Nanocrystals

At present about 40% ofthe drugs being in thedevelopment pipelinesare poorly soluble, even

up to 60% of compounds coming di-rectly from synthesis are poorly solu-ble [1]. Poor solubility is in most casesassociated with poor bioavailability.According to the Noyes-Whitney lawthe dissolution velocity dc/dtdepends on the saturation sol-ubility cs. There are two basicapproaches to overcome thebioavailability problems ofthese drugs:1. Increase of saturation solu-

bility (e.g. by complex for-mation)

2. Increase of dissolutionvelocity.

The first approach was oflimited successs as clearlydemonstrated by the low num-ber of products on the marketbased on such technologies. Amuch more straight forward

*F. N. Bushrab and R. Müller, Department of Pharmaceutics, Biotechnology and Quality Management, Free University of Berlin, Kelchstraße 31, 12169 Berlin, Germany

next step taken was nanonisation.Thedrug powder is transferred to drugnanocrystals, typical sizes are around200 - 600 nm.

The main production technologiescurrently in use to produce drugnanocrystals yield as a product a dis-persion of drug nanocrystals in a liquid,typically water (so called“nanosuspen-

sion”). However, the most con-venient dosage form for the pa-tient is a dry product, e.g. tabletor capsule.This paper describesthe formulation of drugnanocrystals to tablets andcap-sules.

Materials and methodsAmphotericin B was ob-

tained from B. Braun Melsun-gen AG (Melsungen, Germany),polyethylene glycoles of differ-ent molecular weight werekindly supplied by BASF (Lud-wigshaven, Germany). Ho-mogenisation was performed

way is increasing the dissolution veloc-ity by increasing the surface area of thedrug powder, i.e. micronisation leadingto mean particle sizes of approximate-ly 3 - 5 µm. However, many of the newcompounds show such a low solublili-ty that micronisation does not lead toa sufficient increase in bioavailabilityafter oral administration.Therefore the

The number of poorly soluble

drugs – in classical and

pharmabiotech NCEs – is

steadily increasing. A poor

solubility is generally associ-

ated with poor bioavailabili-

ty. Nanocrystals are a novel

formulation approach for

these compounds, this paper

describes production of pa-

tient-convenient oral dosage

forms.

Nanocrystals of PoorlySoluble Drugs for OralAdministration

Faris Nadiem Bushrab*, Rainer H. Müller*

1 PCS diameter and poly-

dispersity index of Ampho-

tericin B nanosuspension in

PEG 400 and PEG 1000 as

a function of homogenisa-

tion cycles (homogenisation

pressure: 1500 bar)

2 Laser diffractometry size distributions of the Amphothericin B powder

in PEG 400 prior homogenisation and after homogenisation with 25 cycles

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Nanocrystals

capsules, e.g. by using the aqueousnanosuspension as granulation fluid inthe tablet production process.One vari-ant of the Nanopure technology is toproducedrugnanocrystals dispersedinliquid PEG or in oils. The obtained sus-pensions can directly be filled into softgelatine capsules or into hard gelatineor HPMC capsules which are then beingsealed. In addition drug nanocrystals insolid PEG can be used as powder fortablet production.

Amphotericin B powder wasdipersed in liquid PEG 400 resp. in melt-ed solid PEG 1000 and homogenised at1500 bar up to 25 homogenisation cy-cles.Figure 1 shows the decrease in PCS

particle size as a function of the cyclenumber. As can be seen, a distinct re-duction in particle size was already ob-tained after one homogenisation cycle.The mean diameter changes little fromcycle 10 to cycle 25,however during fur-ther cycles the fraction of remainingmicroparticles is further reduced.Afineproduct was obtained after 25 ho-mogenisation cycles with a PCS diam-eter of 299 nm (PEG 400) resp. a PCS di-ameter of 331 nm (PEG 1000) and laserdiffractometry diameters 25% of 0.147µm, diameter 50% of 0.258 µm and di-ameter 99% of 2.251 µm (PEG 400). Fig-ure 2 shows the size distribution of thestartingmaterialandahomogenisedfi-nal product,table 1 gives the diameters.Production of tablets

Homogenisation can be performedin polyethylene glycoles being liquid atroom temperature,e.g.PEG 200 and PEG400 typically usedfor capsule filling.Al-ternatively semisolid or solid PEG canbe used, e.g. PEG 1000 or PEG 6000, both

using a lab scale Micron LAB 40 (APVSystems, Unna, Germany). Particle sizeanalysis was performed by photon cor-relation spectroscopy using a Master-sizer 4 (Malvern Instruments, Malvern,U.K.) and laser diffractometry using aCoulter LS 230 (Beckman Coulter,Krefeld,Germany).PCS yields the meandiameter of the bulk population(z-average) and a polydispersity indexquantifying the width of the size dis-tribution. The polydispersity index (PI)ranges from theoretically 0 (monodis-perse population) to 0.50 (relativelybroad distribution), e.g. fat emulsionsfor parenteral nutrition have PI valuesbetween 0.10 and approximately 0.25.Laser diffractometry yields a volumedistribution, the diameters d25%,d50%and d99% were taken as characterisa-tion values for the size distribution.

Results and discussionProduction of drug nanocrystals(Nanopure)

Drug nanocrystals can be producedby bottom up techniques (i.e. precipita-tion) [2] or alternatively by bottomdown technique (i.e. disintegration,milling).Thebottom up techniqueis theclassical precipitation approach, thedrug is dissolved in a solvent which issubsequently added to a nonsolvent toprecipitate the crystals. A priori thistechnique is difficult to handle, thecrystal growth needs to be stopped toavoid formation of microcrystals. In ad-dition this technology cannot be ap-plied to the increasing number of drugsbeeing poorly soluble in all media.Fromthis,disintegration technologies are themethod of choice for industrial pro-duction.

There are three basic technologiescurrently in use owned by differentcompanies:1. Pearl milling (Nanocrystals – élan

prev. Nanosystems) [3, 4]2. Homogenisation in water

(Dissocubes - SkyePharma;Nanoedge - Baxter) [5, 6]

3. Homogenization in nonaqueousmedia or in water with water misci-ble liquids (Nanopure - PharmaSolBerlin) [7-13]

Approaches 1 und 2 yield aqueousnanosuspensions, the water needs tobe removed to formulate tablets and

3 Amphotericin B nanosuspension in liquid PEG

400 (left), as solid dispersion in solidified PEG

1000 (middle) and in form of milled solid PEG

1000 yielding a powder (right)

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Nanocrystals

step is to transfer the aqueousnanosuspensions in a solid dosageform which releases thedrugnanocrys-tals again as ultrafine dispersion. Itneeds to be avoided that excipientsused in the formulation lead to aggre-gation or let crystals fuse under thecompactionpressure usedin tabletting.The company NanoSystems coulddemonstrate in an impressive way pos-

sible achievements in increasing thebioavailability (e.g. Danazol nanosus-pension 82.3%, Danazol microcrystals5.2% bioavailability (Ref. NanoSys-tems)). However NanoSystems couldalso show a strong reduction inbioavailability improvement when ag-gregated nanosuspensions are admin-istered (Ref. Liversidge IIR Köln). Themean PCS diameter of the drugnanocrystals in liquid PEG 400 beforesolidification of the melt was 299 nm,after dissolutionof solidifiedPEGin wa-ter adiameter of 286 nm was measured.

ConclusionsThe productions of drug nanocrys-

tals in non-aqueous media leads to a

also suitable for capsule filling. In thiscase the solid PEG is melted by heatingto 85°C, the drug powder is dispersedand the obtained pre-suspensions arehomogenised at 85°C. This results in ahot nanodispersion which solidifies toa block of PEG. It is a solid dispersion ofdrug nanocrystals in solid PEG as outerphase. In a subsequent step milling canbe performed yielding a flowable pow-der (Figure 3 and 4).

The powder can be admixed to astandard mixture used for direct com-pression.This is the most cost effectiveway to produce tablets containingnanocrystals.Production of capsules

As lined out above, the liquid PEGnanosuspensions can be filled into softgelatine capsules or alternatively intohard gelatine capsules which are sub-seqeuntly being sealed. Production ofsoft gelatine capsules is a more sophis-ticated technology, easier to perform isfilling of hard capsules. Sealing is rela-tively easy to perform when applyingthe smart filling and sealing technolo-gy developped by Capsugel. However,still easier is the filling with a solid ma-terial requiring no sealing. Figure 5 (up-per) shows capsules produced by fillingthe hot PEG nanosuspension directlyinto hard gelatine capsules which sub-sequently then solidify in the capsule.Alternatively the drug nanocrystal con-taining PEG powder was filled into thecapsules (Figure 5, lower).Release of nanocrystals from soliddosage forms

Production of drug nanosuspen-sions using the above mentioned tech-niques is very straight forward. Espe-cially homogenisation is a very simpleproduction technique. A more difficult

5 Capsules directly filled with hot PEG nanosus-

pension (upper) and with granulated solidified

PEG nanosuspension (lower)

more information

bushrab@web.de

www.new-drugs.com� info about publications, research

team and topics of PhD theses� details on technologies,

products, IP

Laser diffractometry diameters beforeand after homogenisation

Volume before after % homogenisation homogenisation

25 5.154 µm 0.147 µm50 7.649 µm 0.258 µm99 32.63 µm 2.251 µm

Table 1

4 Appearance of solid PEG nanocrystal dispersion

milled to a fine powder

smart intermediateproduct for straightforward production of the final dosageform capsule or tablet. One importantquality criterium is the release of thedrug nanocrystals as fine dispersion.

References[1] E. Merisko-Liversidge, Nanocrystals: Resolvingpharmaceutical formulation issues associated withpoorly water-soluble compounds, Particles 2002, 20-23 April 2002, Orlando Florida,paper 45[2] H. Sucker, P. Gassmann, Improvements in phar-maceutical compositions, GB Pat.: 2269536A. 1994,Sandoz LTD. Ch: GB[3] Gary G. Liversidge, Kenneth C. Cundy, John F.Bishop, David A. Czekai, NANOSYSTEMS LLC. Sur-face modified drug nanoparticles. US Pat.: 5,145,684;Sept. 8, 1992[4] Gary G. Liversidge, Kenneth C. Cundy, Particle sizereduction for improvement of oral bioavailability of hy-drophobic drugs: I. Absolute oral bioavailabilty ofnanocrystalline danazol in beagle dogs. InternationalJournal of Pharmaceutics 125 (1995) 91-97; ELSEVIER[5] R. H. Müller, R. Becker, B. Kruss, K. Peters, ddsDrug Delivery, Pharmaceutical nanosuspensions formedicament administration as systems with in-creased saturation solubility and speed of dissolu-tion, Pat.: AU0003982795A[6] J. E. Kipp, J. C. Tak Wong, M. J. Doty, C. L. Rebbeck,BAXTER INTERNATIONAL INC., Microprecipitationmethod for preparing submicron suspensions, USPat. application no. 20020168402 A1, Nov. 14, 2002 [7] Müller, R.H., K. Mäder, K. Krause, PharmaSolGmbH, Dispersions for formulation slightly or poorlysoluble active ingredients. Pat.: CA0002388550A1,Feb. 7., 2002 [8] Radtke, M., Nanopure TM: pure drug nanoparti-cles for the formulation of poorly soluble drugs. New-Drugs, 2001. 3: p. 62-68[9] Müller, R.H. Nanopure technology for the produc-tion of drug nanocrystals and polymeric particles. 4thWorld Meeting ADRITELF/APV/APGI. 2002. Florence[10] Müller, R.H., Jacobs, C., Kayser, O., DissoCubes -a novel formulation for poorly soluble and poorlybioavailable drugs, in Modified-Release Drug Deliv-ery Systems, M.J. Rathbone, Hadgraft, J., Roberts, M.S., Editor. 2003, Marcel Dekker. p. 135-149[11] A. Akkar, R. H. Müller, Nanocrystals of Itracona-zole and amphotericin B produced by high pressurehomogenisation. Annual Meeting of the AmericanAssociation of Pharmaceutical Scientists, Oct. 2003,Salt Lake City [12] Müller, R.H., Böhm, B.H.L., Grau, M., Nanosus-pensionen - Formulierungen für schwerlöslicheArzneistoffe mit geringer Bioverfügbarkeit: I Herstel-lung und Eigenschaften, Pharm. Ind., 74-78, 1999[13] Müller, R. H., Böhm, B. H. L., Grau, M. J.,Nanosuspensionen - Formulierungen für schwerlös-liche Arzneistoffe mit geringer Bioverfügbarkeit: II.Stabilität, biopharmazeutische Aspekte, möglicheArzneiformen und Zulassungsfragen, Pharm. Ind. 61(2), 175-178, 1999

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