} dispersion sci technol svenson s ed carrierbased drug delivery vol acs symposium series, american chemical society, washington, dc a tomalia da birth of a new macromolecular architecture dendrimers as quantized building blocks for nanoscale synthetic levaquin cymbalta interaction organic chemistry aldrichimica acta b tomalia da birth of a new macromolecular architecture dendrimers as quantized building blocks for nanoscale synthetic polymer chemistry prog polym sci c tomalia da the dendritic state materials today march d tomalia da levaquin cymbalta interaction dendrimeric supramolecular and supramacromolecular assemblies, in supramolecular polymers, nd ed, crc press, taylor & francis, boca raton, fl tomalia da and frechet jmj eds dendrimers and other dendritic polymers j wiley & sons ltd, chichester a watkins dm, sayedsweet y, klimash jw, turro nj and tomalia da dendrimers with hydrophobic cores and the formation of supramolecular dendrimer � surfactant assemblies langmuir b 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of herpes simplex virus replication antiviral res witvrouw m, fikkert v, pluymers w, matthews b, mardel k, schols d, raff j, debyser z, declercq e, holan g and pannecouque levaquin cymbalta interaction � polyanionic ie polysulfonate dendrimers can inhibit the replication of human immunodeficiency virus by interfering with both virus adsorption and later steps reverse transcriptaseintegrase in the virus replicative cycle mol pharmacol chen cz and cooper sl interactions between levaquin cymbalta interaction dendrimer biocides and bacterial membranes biomaterials chen cz, becktan nc, dhurjati p, van dyk tk, larossa ra and cooper sl quaternary ammonium functionalized polypropylene imine dendrimers as effective antimicrobials structureactivity studies biomacromol nagahori n, lee rt, nishimura levaquin cymbalta interaction s, page d, roy r and lee yc inhibition of adhesion of type fimbriated escherichia coli to highly mannosylated ligands chem biochem sashiwa h and aiba si chemically modified chitin and chitosan as biomaterials prog polymer sci lebreton s, newcombe n and bradley m antibacterial singlebead screening tetrahedron solassol j, crozet c, perrier v, leclaire j, beranger f, caminade am, meunier b, dormont d, majoral jp and lehmann s cationic phosphoruscontaining dendrimers reduce prion replication both in cell culture and in mice infected with scapie j gen virol elsayed m, rhodes ca, ginski m and ghandehari h transport mechanisms of polyamidoamine dendrimers across caco cell monolayers int} pharm demanuele a, jevprasesphant r, penny j levaquin cymbalta interaction and attwood d the use of a dendrimerpropanolol prodrug to bypass efflux transporters and enhance oral bioavailability j control rel chauhan as, sridevi s, chalasani kb, jain ak, jain sk, jain nk and diwan pv dendrimermediated transdermal levaquin cymbalta interaction delivery enhanced bioavailability of indomethacin j control rel wang zx, itoh ys, hosaka y, kobayashi i, nakano y, maeda i, umeda 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fischer d, li y, ahlemeyer b, krieglstein j and kissel t in vitro cytotoxicity testing of polycations influence of polymer structure on cell viability and hemolysis biomaterials malik n, wiwattanapatapee r, klopsch r, levaquin cymbalta interaction lorenz k, frey h, weener jw, meijer ew, paulus w and duncan r dendrimers relationship between structure and bio compatibility in vitro, and preliminary studies on the biodistribution of ilabelled polyamidoamine dendrimers in vivo} control rel zinselmeyer bh, levaquin cymbalta interaction mackay sp, schatzlein ag and uchegbu if the lower generation polypropylenimine dendrimers are effective genetransfer agents pharm res kubasiak la and tomalia da manuscript in preparation yoo h and juliano rl enhanced delivery of antisense oligonucleotides with fluorophoreconjugated levaquin cymbalta interaction ����� dendrimers nucleic acids res roberts jc, bhalgat mk and zera rt preliminary biological evaluation of polyamidoamine ����� starburst dendrimers j biomed mater res kobayashi h, kawamoto s, saga t, sato n, hiraga a, ishimori t, konishi j, levaquin cymbalta interaction togashi � and brechbiel mw positive effects of polyethylene glycol conjugation to generation polyamidoamine dendrimers as macromolecular mr contrast agents magn reson med tomalia da and frechet jmj discovery of dendrimers and dendritic polymers a brief historical perspective levaquin cymbalta interaction j polym sci part a polym chem drug nanocrystalsnanosuspensions for the delivery of poorly soluble drugs rainer h muller and jensuwe a h junghanns introduction since the last ten years, the number of poorly soluble drugs is levaquin cymbalta interaction steadily increasing according to estimates, about of the drugs in the pipelines have solubility problems the increased use of high throughput screening methods leads to the discovery of more drugs being poorly water soluble in the literature, figures levaquin cymbalta interaction are quoted that about percent of the drugs coming directly from synthesis are nowadays poorly soluble poor solubility is not only a problem for the formulation development and clinical testing, it is also an obstacle at the very beginning when screening new compounds for pharmacological activity from this, there is a definite need for smart technological formulation approaches to make such poorly soluble drugs bioavailable making such drugs bioavailable means that they show sufficiently high absorption levaquin cymbalta interaction after oral administration, or they can alternatively be injected intravenously there is quite a number of formulation approaches for poorly soluble drugs which can be specified as specific approaches these approaches are suitable for molecules having special properties levaquin cymbalta interaction with regard to their chemistry eg solubility in certain organic media or to the molecular size or conformation eg molecules to be incorporated into the cyclodextrin ring structure of course it would be much smarter to have levaquin cymbalta interaction a universal formulation approach applicable to any molecule such a universal formulation approach to increase the oral bioavailability is micronization, meaning the transfer of drug powders into the size range between typically �� however, nowadays many drugs are levaquin cymbalta interaction so poorly soluble that micronization is not sufficient the increase in surface area, and thus consequently in dissolution velocity, is not sufficient to overcome the bioavailability problems of very poorly soluble drugs of the biopharmaceutical specification class ii levaquin cymbalta interaction a consequent next step was to move from micronization to nanonization since the beginning of the s, the company nanosystems propagated the use of nanocrystals instead of microcrystals for oral bioavailability enhancement, and also to use nanocrystals suspended levaquin cymbalta interaction in water nanosuspensions for intravenous or pulmonary drug delivery the solution was simple in general, simple solutions possess the smartness that they can be realized easier than complex systems and introduction to the market is faster nevertheless, levaquin cymbalta interaction it took about ten years before the first nanocrystals in a tablet appeared on the market, the product rapamune� by the company wyeth in compared with liposomes developed in with the first products on the market around eg alveofact�, a lung surfactant, this was still relatively fast what were the reasons that it took about one decade for nanocrystals to enter the market from our point of view, pharmaceutical companies prefer to use formulation technology already levaquin cymbalta interaction established with know how available in the company in addition, if formulation technologies are established, a company also has the possibility for production of the final product therefore, all the traditional formulation approaches were exploited to solve a formulation problem in addition, formulation approaches were preferred, being even simpler than nanocrystals for example, production of drugcontaining microemulsions administered in a capsule is, in many cases, even simpler another reason for the reluctance of pharmaceutical companies at levaquin cymbalta interaction the beginning was the lack of large scale production methods these were not available at the very beginning of the development of the nanocrystal technology meanwhile, this has changed and the major pharmaceutical companies try to secure levaquin cymbalta interaction or have already secured their access to nanocrystal technology access to nanocrystal technology is possible either by licencing in or alternatively by the attempt to develop ones own production technologies for the nanocrystals, which do not depend on levaquin cymbalta interaction already existing intelectual property ip this chapter discusses the physicochemical properties of nanocrystals which make them interesting for drug delivery, reviews and discusses briefly the various production methods available and highlights the opportunities for improved drug delivery using different application routes definitions drug nanocrystals are crystals with a size in the nanometer range, meaning that they are nanoparticles with a crystalline character there are discussions about the definition of a nanoparticle, referring to the size of levaquin cymbalta interaction a particle to be classified as a nanoparticle depending on the discipline, eg in colloid chemistry, particles are only considered as nanoparticles when they are in sizes below nm or even below nm based on the size unit, levaquin cymbalta interaction in the pharmaceutical area, nanoparticles should be defined as having a size between a few nanometers and nm im thus, microparticles possess consequently a size micrometer a further characteristic is that drug nanocrystals are composed of drug levaquin cymbalta interaction there is no carrier material as in polymeric nanoparticles dispersion of drug nanocrystals in liquid media leads to nanosuspensions, in contrast to micro suspensions or macrosuspensions in general, the dispersed particles need to be stabilized, eg by surfactants levaquin cymbalta interaction or polymeric stabilizers dispersion media can be water, aqueous solutions or nonaqueous media [eg liquid polyethylene glycol peg, oils] depending on the production technology, processing of drug micro crystals to drug nanoparticles can lead to either a crystalline levaquin cymbalta interaction or to an amorphous product, especially when applying precipitation in the strict sense, such an amorphous drug nanoparticle should not be called nanocrystal however, one often refers to nanocrystals in the amorphous state physicochemical properties of drug nanocrystals levaquin cymbalta interaction change of dissolution velocity the reason for micronization is to increase the surface area, thus consequently according to the noyeswhitney equation, increasing the dissolution velocity therefore, micronization can be succesfully employed if the dissolution velocity is the ratelimiting step for oral absorption drugs of bsc ii of course, by moving one dimension further to smaller particles, the surface area is further enlarged and consequently, the dissolution velocity is further enhanced in most cases, a low levaquin cymbalta interaction dissolution velocity is correlated with a low saturation solubility saturation solubility the general textbook statement is that the saturation solubility cs is a constant depending on the compound, the dissolution medium and the temperature this is valid for levaquin cymbalta interaction powders of daily life with a size in the micrometer range or above however, below a critical size of �m, the saturation solubility is also a function of the particle size it increases with decreasing particle size below levaquin cymbalta interaction nm therefore, drug nanocrystals possess an increased saturation solubility this has two advantages according to noyeswhitney, the dissolution velocity is further enhanced because dcdt is proportional to the concentration gradient cs � cxh cx � bulk concentration, h levaquin cymbalta interaction � diffusional distance due to the increased saturation solubility, the concentration gradient between gut lumen and blood is increased, consequently, the absorption by passive diffusion the interesting question very often asked is how manyfold is the increased saturation solubility?