} 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 effexor prescribed for pain 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 effexor prescribed for pain 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, effexor prescribed for pain sayedsweet y, klimash jw, turro nj and tomalia da dendrimers with hydrophobic cores and the formation of supramolecular dendrimer � surfactant assemblies langmuir b sayedsweet y, hedstrand dm, spinder r and tomalia da hydrophobically modified polyamidoamine ����� dendrimers effexor prescribed for pain their properties at the airwater interface and use as nanoscopic container molecules j mater chem recker j, tomcik dj and parquette jr folding dendrons the development of solvent, temperature, and generationdependent chiral conformational order in intramolecularly hydrogenbonded effexor prescribed for pain dendrons j am chem soc boas u, karlsson aj, de waal bfm and meijer ew synthesis and properties of new thioureafunctionalized polypropylene imine dendrimers and their role as hosts for urea functionalized guests ] org chem tomalia da, effexor prescribed for pain naylor am and goddard iii wa starburst dendrimers molecular level control of size, shape, surface chemistry, topology and flexibility from atoms to macroscopic matter angew chem int ed engl naylor am, goddard iii wa, kiefer ge and tomalia effexor prescribed for pain da starburst dendrimers molecular shape control } am chem soc jansen jfga, debrabandervandenberg emm and meijer ew encapsulation of guest molecules into a dendritic box science jansen jfga, meijer ew and debrabandervandenberg emm the dendritic box shapeselective liberation effexor prescribed for pain of encapsulated guests j am chem soc a esfand r and tomalia da polyamidoamine ����� dendrimers from biomimicry to drug delivery and biomedical applications drug disc today b tomalia da, hall m, hedstrand starburst� dendrimers iii the importance of branch junction symmetry in the development of topological shell molecules } am chem soc twyman lj, beezer ae, esfand r, hardy mj and mitchell jc the synthesis of watersoluble dendrimers, and their application as possible drug effexor prescribed for pain delivery systems tetrahedron lett gorman cb and smith jc structureproperty relationships in dendritic encapsulation acc chem res chasse tl, yohannan jc, kim n, li q, li z and estrace stomach upset gorman cb dendritic encapsulationroles of cores and branches tetrahedron chasse tl, sachdeva r, li q, li z, petrie rj and gorman cb structural effects on encapsulation as probed in redoxactive core dendrimer isomers } am chem soc wallimann p, marti t, furer a and diederich f steroids in molecular recognition chem rev wallimann p, seiler p and diederich f dendrophanes novel steroidrecognizing dendritic receptors helv chim acta smith dk, zingg a and diederich f dendroclefts optically active dendritic receptors for the selective recognition and chiroptical sensing effexor prescribed for pain of monosaccharide guests helv chim acta smith dk and diederich f dendritic hydrogen bonding receptors enantiomeri cally pure dendroclefts for the selective recognition of monosaccharides chem commun zimmerman sc, wendland ms, rakow na, zharov i and suslick ks effexor prescribed for pain synthetic hosts by monomolecular imprinting inside dendrimers nature broeren mac, van dongen jlj, pittelkow m, christensen jb, van genderen ��� and meijer ew multivalency in the gas phase the study of dendritic aggregates by mass spectrometry angew effexor prescribed for pain chem int ed maeda h and matsumura y a new concept in macromolecular therapeutics in cancer chemotherapy mechanism of tumoritropic accumulation of proteins and antitumor agent smancs cancer res boas u and heegaard pmh dendrimers in drug research effexor prescribed for pain chem soc rev frechet jmj designing dendrimers for drug delivery pharm sci technol today gillies er and frechet jmj dendrimers and dendritic polymers in drug delivery drug disc today malik n, evagorou eg and duncan r dendrimerplatinate a effexor prescribed for pain novel approach to cancer chemotherapy anticancer drugs a malik n and duncan r dendriticplatinate drug delivery system us b malik n and duncan r method of treating cancerous tumors with a dendriticplatinate drug delivery system us c malik effexor prescribed for pain n, duncan r, tomalia da, esfand r dendriticantineoplastic drug delivery system us patents owned by dendritic nanotechnologies, inc dnt kelland lr and farrell np eds platinumbased drugs in cancer chemotherapy humana press totowa, nj gianasi e, wasil m, effexor prescribed for pain evagorou eg, keddle a, wilson g and duncan r hpma copolymer platinates as novel antitumor agents in vitro properties, pharmacokinetics and antitumor activity in vivo eur j cancer balogh l, swanson dr, tomalia da, hagnauer gl and effexor prescribed for pain mcmanus at dendrimer silver complexes and nanocomposites as antimicrobial agents nano lett kojima c, kono k, maruyama � and takagishi t synthesis of polyamidoamine dendrimers having polyethylene glycol grafts and their ability to encapsulate anticancer drugs bioconjug chem effexor prescribed for pain pan gf, lemmouchi y, akala eo and bakare � studies on pegylated and drug loaded ����� dendrimers f bioactive compat polym bhadra d, bhadra s, jain s and jain nk a pegylated dendritic nanoparticulate carrier of fluorouracil int effexor prescribed for pain j pharm wang f, bronich tk, kabanov av, rauh rd and roovers j synthesis and evaluation of a star amphiphilic block copolymer from poly ecaprolactone and polyethylene glycol as a potential drug delivery carrier bioconjug chem namazi h effexor prescribed for pain and adell m dendrimers of citric acid and polyethylene glycol as the new drug delivery agents biomaterials yang h and lopina st extended release of a novel antidepressant, venlafaxine, based on anionic polyamidoamine dendrimers and polyethylene glycolcontaining effexor prescribed for pain semiinterpenetrating networks j biomed mater res part a a kolhe p, misra e, kannan rm, kannan s and liehlai m drug complexation, in vitro release and cellular entry of dendrimers and hyperbranched polymers int j pharm kannan s, effexor prescribed for pain kolhe p, raykova v, glibatec m, kannan rm, liehlai m and bassett d dynamics of cellular entry and drug delivery by dendritic polymers into human lung epithelial carcinoma cells j biomater sci polym ed chauhan as, jain nk, effexor prescribed for pain diwan pv and khopade aj solubility enhancement of indomethacin with polyamidoamine dendrimers and targeting to inflammatory regions of arthritic rats j drug targ kubasiak la, chauhan as and tomalia da manuscript in preparation devarakonda b, hill ra and effexor prescribed for pain de villiers mm the effect of ����� dendrimer generation size and surface functional group on the aqueous solubility of nifedipine int} pharm potluri sk, ramulu ar and pardhasaradhi m synthesis of new unsymmetrical optically active snaproxen tetrahedron ooya effexor prescribed for pain t, lee j and park � hydrotropic dendrimers of generations and synthesis, characterization, and hydrotropic solubilization of paclitaxel bioconjug chem khandare j, kolhe p, pillai o, kannan s, liehlai m and kannan rm synthesis, cellular transport, and activity of polyamidoamine dendrimermethylprednisolone conjugates bioconjug chem shamis m, lode hn and shabat d bioactivation of selfimmolative dendritic prodrugs by catalytic antibody c } am chem soc haba k, popkov m, shamis m, lerner ra, barbas iii cf effexor prescribed for pain and shabat d single triggered trimeric prodrugs angew chem int ed padilla de jesus ol, ihre hr, gagne l, frechet jmj and szoka jr fc polyester dendritic systems for drug delivery applications in vitro and in vivo evaluation effexor prescribed for pain bioconjug chem nishiyama n, stapert hr, zhang gd, takasu d, jiang dl, nagano t, aida t and kataoka � lightharvesting ionic dendrimer porphyrins as new photosensitiz ers for photodynamic therapy bioconjug chem zhang gd, harada a, nishiyama n, effexor prescribed for pain jiang dl, koyama h, aida t and kataoka � polyion complex micelles entrapping cationic dendrimer porphyrin effective photosensitizer for photodynamic therapy of cancer j control rel jang wd, nishiyama n, zhang gd, harada a, jiang dl, kawauchi s, morimoto y, kikuchi m, koyana h, aida t and kataoka � supramolecular nanocarrier of anionic dendrimer porphyrins with cationic block copolymers modified with polyethylene glycol to enhance intracellular photodynamic efficacy angew chem int ed battah sh, chee effexor prescribed for pain ce, akanishi h, gerscher s, macrobert aj and edwards � synthesis and biological studies of aminolevulinic acidcontaining dendrimers for photodynamic therapy bioconjug chem paul a, hackbarth s, molich a, luban c, oelckers s, bohm f and roder � effexor prescribed for pain comparative study of the photosensitization of jurkat cells in vitro by pheophorbide a and a pheophorbide adiaminobutane polypropylene imine dendrimer complex laser phys wu g, barth rf, yang wl, chatterjee m, tjarks w, ciesielski mj and fenstermaker ra effexor prescribed for pain sitespecific conjugation of boroncontaining dendrimers to antiegf receptor monoclonal antibody cetuximab imcc and its evaluation as a potential delivery agent for neutron capture therapy bioconjug chem shukla s, wu g, chatterjee m, yang wl, sekido m, diop la, muller r, sudimack jj, lee rj, barth rf and tjarks w synthesis and biological evaluation of folate receptortargeted boronated ����� dendrimers as potential agents for neutron capture therapy bioconjug chem kono k, liu m and frechet jmj design effexor prescribed for pain of dendritic macromolecules containing folate or methotrexate residues bioconjug chem quintana a, raczka e, piehler l, lee i, ��� a, majoros i, patri ak, thomas t, mule j and baker jr jr design and function of a effexor prescribed for pain dendrimerbased therapeutic nanodevice targeted to tumor cells through the folate receptor pharm res ross jf, chaudhuri pk and ratnam m differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and established cell lines physiologic effexor prescribed for pain and clinical implications cancer tansey w, ke s, cao xy, pasuelo mj, wallace s and li � synthesis and characterization of branched polylglutamic acid as a biodegradable drug carrier } control rel lundquist jj and toone ej the effexor prescribed for pain cluster glycoside effect chem rev zanini d and roy r synthesis of new athiosialodendrimers and their binding properties to the sialic acid specific lectin from limax flavus am chem soc bezouska k, pospisil mf, vannucci lf, fiserova af, effexor prescribed for pain krausova kf, horvath of, kren vf, mosca ff, lindhorst tk, sadalapure kf and bezouska � design, functional evaluation and biomedical applications of carbohydrate dendrimers glycodendrimers rev mol biotechnol roy r syntheses and some applications of chemically defined effexor prescribed for pain multivalent gly coconjugates curr opin struct biol lindhorst tk artificial multivalent sugar ligands to understand and manipulate carbohydrateprotein interactions top curr chem hostguest chem rockendorf n and lindhorst tk glycodendrimers top curr chem dend iv veprek p and effexor prescribed for pain jezek j peptide and glycopeptide dendrimers part ii j pept sci andre s, pieters rj, vrasidas i, kaltner h, kuwabara i, liu ft, liskamp rm and gabius hj wedgelike glycodendrimers as inhibitors of binding of mammalian galectins to effexor prescribed for pain glycoproteins, lactose maxiclusters, and cell surface glycoconjugates chembiochem pieters rj interference with lectin binding and bacterial adhesion by multivalent carbohydrates and peptidic carbohydrate mimics trends glycosci glycotechnol baek mg and roy r synthesis and protein binding properties of effexor prescribed for pain tantigen containing glycopamam dendrimers bioorg med chem roy r, baek mg and rittenhouseolson � synthesis of n,n bisacrylamidoacetic acidbased tantigen glycodendrimers and their mouse monoclonal igg antibody binding properties j am chem soc roy r and baek effexor prescribed for pain mg glycodendrimers novel glycotope isosteres unmasking sugar coating case study with tantigen markers from breast cancer muc glycoprotein rev mol biotechnol benito im, gomezgarcia m, mellet co, baussanne i, defaye j and fernandez jmg optimizing saccharidedirected molecular effexor prescribed for pain delivery to biological receptors design, synthesis, and biological evaluation of glycodendrimercyclodextrin conjugates j am chem soc hansen hc, haataja s, finne j and magnusson g di, tri, and tetravalent dendritic galabiosides that inhibit hemagglutination by streptococcus suis at effexor prescribed for pain nanomolar concentration } am chem soc rendle pm, seger a, rodrigues j, oldham nj, bott rr, fones jb, cowan mm and davies bg glycodendriproteins a synthetic glycoprotein mimic enzyme with branched sugardisplay potently inhibits bacterial aggregation j am effexor prescribed for pain chem soc shaunak s, thomas s, gianasi e, godwin a, jones e, teo i, mireskandari k, luthert p, duncan r, patterson s, khaw p and brocchini s polyvalent dendrimer glucosamine conjugates prevent scar tissue formation nat biotech thomas effexor prescribed for pain tp, patri ak, ��� a, myaing mt, ye jy, norris �� and baker jr jr in vitro targeting of synthesized antibodyconjugated dendrimer nanoparticles biomacro mol hong my, yoon hc and kim hs proteinligand interactions at poly amidoamine dendrimer effexor prescribed for pain monolayers on gold langmuir sanchezsancho f, perezinestrosa e, suau r, mayorga c, torres mj and blanca m dendrimers as carrier protein mimetics for ige antibody recognition synthesis and characterization of densely penicilloylated dendrimers bioconjug chem yang h effexor prescribed for pain and lopina st penicillin vconjugated pegpamam star polymers j biomater scipolym ed bourne n, stanberry lr, kern er, holan g, matthews � and bernstein di dendrimers, a new class of candidate topical microbicides with activity against herpes simplex effexor prescribed for pain virus infection antimicrob agents chemother product focus vivagel, starpharma limited, melbourne, australia gong y, matthews b, cheung d, tarn t, gadawski i, leung d, holan g, raff j and sacks s evidence of dual sites of action of dendrimers spl inhibits both virus entry and late stages 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 � 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain delivery enhanced bioavailability of indomethacin j control rel wang zx, itoh ys, hosaka y, kobayashi i, nakano y, maeda i, umeda f, yamakawa j, kawase m and yagi � novel transdermal drug delivery system with polyhydroxyalkanoate and starburst effexor prescribed for pain polyamidoamine dendrimer j biosci bioeng wang zx, itoh ys, hosaka y, kobayashi i, nakano y, maeda i, umeda f, yamakawa j, nishimine m, suenobu t, fukuzumi s, kawase m and yagi � mechanism of enhancement effect of dendrimer on transdermal drug permeation through polyhy droxyalkanoate matrix j biosci bioeng vandamme tf and brobeck l polyamidoamine dendrimers as ophthalmic vehicles for ocular delivery of pilocarpine nitrate and tropicamide j control rel jevprasesphant r, penny j, jalal r, effexor prescribed for pain attwood d, mckeown nb and demanuele a the influence of surface modification on the cytotoxicity of ����� dendrimers int j pharm elsayed m, ginski m, rhodes � and ghandehari h transepithelial transport of polyamidoamine dendrimers across caco cell effexor prescribed for pain monolayers } control rel 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, effexor prescribed for pain 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, effexor prescribed for pain 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 ����� 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, effexor prescribed for pain 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 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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 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 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 effexor prescribed for pain 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, effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain formulation problem in addition, top 10 apris ski 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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, effexor prescribed for pain 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 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 effexor prescribed for pain 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 effexor prescribed for pain 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 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain 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 effexor prescribed for pain � 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?