investigated the delivery from a waterinoil microemulsion, of apomorphine present as ionpair complex with octanoate to increase its lipophilicity and to diminish its dissociation as the drug was present at a high concentration, the dispersed phase acted as a reservoir, making it possible to maintain an almost constant concentration in the continuous phase and therefore achieving pseudo zeroorder release kinetics the composition of the microemulsion was complex, containing wt water, wt of oily phase of isopropyl miristatedecanol vv, wt rapomorphine hydrochloride, wt epikuron , wt benzyl alcohol, wt octanoic acid wt sodium octanoate, wt sodium taurocholate, wt ,propanediol the microemulsion was thickened by the addition of wt aerosil the microemulsion was able to provide in vitro, through hairless mouse skin, a flux of gh per cm for hrs, with a kinetic release of pseudozeroorder, and was chosen for in vivo study all the components were biocompatible and safe the flux gave a first approximation of the feasibility of the transdermal administration in man the pain and discomfort caused by the injection of local anesthetics has stimulated research into developing topical anesthetics however, the currently available formulations, such as ametop�gel, wt amethocaine base preparation have a number of disadvantages, in particular a long delay of typically min between application and anesthetic effect and gangrene after penicillin the requirement for a plastic occlusive dressing arevalo et al have recently developed a decaneinwater microemulsion stabilized by lauromacrogol and containing wt of amethocaine in an attempt to achieve faster drug permeation, thus reducing the time to reach optimum anesthetic effect the amethocaine microemulsion proved to be a promising fastacting analgesic in experimental preclinical studies mixtures of hydrophilic and hydrophobic drugs although microemulsions have long been suggested as suitable formulations for the coadminstration of drugs of very varying physicochemical properties, it is only very recently that anyone has reported doing so lee et al have developed a novel microemulsion enhancer formulation for the coadministration of hydrophilic lidocaine hc, diltiazem hc and lipophilic lidocaine free base, estradiol drugs the microemulsions composed of isopropyl myristate and water, and were stabilized by the nonionic surfactant, tween transdermal enhancers such as �methyl pyrroli done nmp and oleyl alcohol were incorporated into all systems without apparent disruption of the system unfortunately, the authors did not give the precise, composition of the microemulsions tested it was only mentioned that they contained a vv mixture of water and ethanol, isopropylmyristate as oil and tween as surfactant, and were either oilinwater or waterinoil interestingly, regardless of the physicochemical nature of the drug, the oilinwater microemulsions provided significantly better flux for all gangrene after penicillin drugs studied p enhancement of drug permeability from the oilinwater systems was fold for lidocaine base, fold for lidocaine hc,fold for estradiol, and fold for diltiazem hc significantly, the simultaneous delivery of estradiol with diltiazem hydrochloride did not affect the transport of either drug p immunization traditionally, vaccines have been administered by injection using needles, although the concept of topical immunization through intact skin has attracted much attention cui et ali recently hypothesized that a fluorocarbonbased microemulsion system could be one possible way to deliver plasmid dna across the skin cui et al screened a range of fluorosurfactants for their ability to form ethanol inperfluorooctyl bromide microemulsions note that the authors provided no evidence of a microemulsion being formed the stability of plasmid dna in the formulations was also examined from the surfactant screen, the commercially available zonyl� fsn, an ethoxylated nonionic fluorosurfactant, was selected for further study significant enhancements in luciferase expression and antibody and thelper type based immune responses, relative to those of naked pdna in saline or ethanol, were observed after topical application of plasmid dna in ethanolinperfluorooctyl bromide microemulsion system from these studies, it can be concluded that fluorocarbonbased microemulsions are suitable for dna vaccine delivery, although the mechanisms of the immune response induction is not known it gangrene after penicillin is possible that the transport of the molecules across the skin is via the hairfollicles, because dna is too large and highly charged to cross intact stratum corneum ophthalmic conventional ophthalmic dosage forms tend to be either simple solutions of water soluble drugs or suspension or ointment formulations of waterinsoluble drugs unfortunately, as these delivery vehicles generally result in poor levels of drug absorption across the cornea, most of the applied drug does not reach its intended site of action however, because of the relative safety and convenience of topical application in ophthalmology, as well as the relatively low risk compared with other routes of administration of systemic sideeffects, topical administration of ophthalmic agents is the preferred route of delivery microemulsions and sub microemulsions should offer a possible solution to the problem of poor delivery to the cornea, by sustaining the release of the drug, as well as by providing a higher penetration of drug into the deeper layers of the eye in addition, they offer the potential of increasing the solubility of the drug in the ophthalmic delivery vehicle gallarate et � were probably the first to examine the potential of microemulsions as vehicles for ophthalmic delivery since then, a number of groups have successfully demonstrated the ability of microemulsions submicroemulsions gangrene after penicillin to prolong the ocular delivery of drug in their study, gallarte et al were able to further prolong the release of timolol by forming an ion pair with octanoic acid garty and lusky demonstrated that the delivery of pilocarpine from an oilin water microemulsion was delayed to such an extent that the instillations of the microemulsion formulation twice daily were equivalent to four times daily the applications of conventional eye drops a similar result was reported by muchtar et al who determined in vitro that the corneal penetration of indomethacin formulated in a submicroemulsion was more than three times that obtained using commercially available drops a number of researcher have investigated the potential of positively charged microemulsions to retain the delivery vehicle in the eye, thereby sustaining delivery to date, a range of drugs have been formulated in a microemulsion in an attempt to sustain release including adaprolol maleate timolol, levobunolol, chloramphenicol tepoxalin, piroxicam, deltatetrahydrocannabinol, pilocarpine, indomethacin, antibodies and dietary isoflavonoids and flavonoids in general, these studies showed that it was possible to delay the effect of drug incorporated in a microemulsion, thereby improving bioavailability the proposed mechanism of the delayed action is that microemulsion droplets are not eliminated by the lachrymal drainage, thereby acting as drug reservoirs the first studies conducted on gangrene after penicillin man with microemulsions containing adaprolol maleate and pilocarpine, confirmed the results of the earlier studies performed mainly using rabbits, vandamme has recently reviewed the use of microemulsions as ocular delivery system, and thus only studies since then will be considered in the present review fialho and da silvacunha recently investigated the long term application of a microemulsion system in rabbits intended for the topical ocular administration of dexamethasone the formulation contained wt isopropyl myristate as oil, wt cremophor el as surfactant, and a polar phase of water and wt propylene glycol, with dexamethasone present at a concentration of wt significantly, ocular irritation tests in rabbits suggested that the microemulsion did not provide significant alteration to eyelids, conjunctiva, cornea and iris over a fe month period in addition, the formulation exhibited greater penetration of dex amethasone in the anterior segment of the eye and longer release of the drug when compared with a conventional preparation the area under the curve obtained for the microemulsion system was more than twofold that of the conventional preparation p gulsen and chauhan have recently developed a disposable soft contact lens of a drugcontaining microemulsion dispersed in a poly hydroxyethyl methacrylate ���� hydrogel, suitable for ophthalmic delivery, in an attempt to reduce drug loss and sideeffects upon insertion into gangrene after penicillin the eye, the lens will slowly release the drug into the pre lens the film between the air and the lens and the postlens the film between the cornea and the lens tear films, thus providing a sustained delivery of drug assuming the size and drug loading of the microemulsions is low, the lenses should be transparent it was found using these microemulsioncontaining lenses, with and without a stabilizing silica shell, that drug could be released for a period of days by altering droplet size and loading, it is possible to tailor release vaginal in their review, dcruz and uckun proposed that microemulsion gel formulations had great potential as intra vaginal rectal drug delivery vehicles for lipophilic drugs, such as microbicides, steroids, and hormones, because of their high drug solubilization capacity, increased absorption, and improved clinical potency, as long as a non toxic formulation could be prepared in their review, dcruz and uckun reported the formulation of two microemulsionbased gels using common ally available pharmaceutical excipients repeated intravaginal applications of formulations to rabbits and mice were found to be safe and did not cause local, systemic, or reproductive toxicity dcruz and uckun investigated the potential of the microemulsionbased gels as delivery vehicles of two lipophilic drugs, whi and whi, which exhibit potent gangrene after penicillin antihiv and contraceptive activity as aids is spread largely through sexual intercourse, the development of a dual action vaginal spermicidal microbicide to curb mucosal viral transmission, as well as to provide fertility control would have a tremendous impact world wide dcruz and uckun investigated the formulation of wt of the lipophilic drugs in a microemulsionbased gel, composed of phospholipon g and captex as the oil phase, with pluronic f and cremophor el as surfactants, and seaspan carra gennan and xantral as gelling agents the microemulsions were gelled to obtain the necessary viscosity for the gelmicroemulsion formulation under the conditions of their intended use, intravaginal application of the gelmicroemulsions containing wt of drug in a rabbit model resulted in marked contraceptive activity, as well as exhibiting a lack of toxicity therefore, as a result of its dual antihiv and spermicidal activities, the drugcontaining gels shows unique clinical potential as a vaginal prophylactic contraceptive for women who are at a high risk of acquiring hiv by heterosexual transmission nasal nasal route has been demonstrated as being a possible alternative to the intravenous route for the systemic delivery of drugs in addition to rapid absorption and avoidance of hepatic firstpass metabolism, the nasal route allows the preferential delivery of drug to the brain via the olfactory gangrene after penicillin region, and is therefore a promising approach for the rapidonset delivery of cms medications the solutionlike feature of microemulsions could provide advantages over emulsions in terms of the sprayability, dose uniformity and formulation physical stability li et alni developed a diazepamcontaining ethyl laurateinwater microemulsion, stabilized by tween and containing propylene glycol and ethanol as cosol vents for the rapidonset intranasal delivery of diazepam a single isotropic region, which was considered to be a bicontinuous microemulsion, was seen at high surfactant concentrations but at various tween propylene glycol ethanol ratios increasing tween concentration increased the microemulsion area, microemulsion viscosity, and the amount of water and oil solubilized in contrast, increasing ethanol concentration produced the opposite effect a microemulsion consisting of wt ethyl laurate, wt water and wt tween propylene glycolethanol at a weight ratio contained mgml of the poorlywater soluble diazepam the nasal absorption of diazepam from the formulation was fairly rapid with a maximum drug plasma concentration being obtained within to min, while bioavailability at hrs postadministration was of that obtained with intravenous injection zhang et al attempted to prepare an oilinwater microemulsion, containing a high concentration of nimodipine, suitable for brain uptake via the intranasal route of delivery three microemulsion systems stabilized by either cremophor rh or labrasol, and containing a variety gangrene after penicillin of oils, namely isopropyl myristate, labrafil m cs and maisine , were developed and characterized the nasal absorption of the drug from the three microemulsions was studied in rats the formulation composed of wt labrafil m cs, wt cremophor rh ethanol weight ratio and water solubilized up to mgml of drug and exhibited no ciliotoxi city after intranasal administration, the peak plasma concentration was obtained of hr, while the absolute bioavailability was significantly, uptake of the drug in the olfactory bulb after nasal administration was three times that which was obtained from intravenous injection in addition, the ratios of the auc in brain tissues and cerebrospinal fluid to that in plasma obtained after nasal administration were significantly higher than those seen after administration in conclusion, the microemulsion system appears to be a promising approach for the intranasal delivery of nimodipine richter and keipert investigated the in vitro permeability of the highly lipophilic material, androstenedione, across excised bovine nasal mucosa, porcine cornea and an artificial cellulose membrane in order to control release, the two microemulsion formulations studied contained either hydroxypropylys cyclodextrin or propylene glycol both microemulsions were prepared from wt isopropyl myristate, wt cremophor el and water the permeation of the drug through the three tissues was influenced by the microemulsion for example, the gangrene after penicillin apparent permeability coefficients papp of the drug from the microemulsions across nasal mucosa did not differ from the papp of the drug contained in solution in the case of the other two membranes, release from both of the microemulsion formulations exhibited extended time lags, so no papp could be calculated it seems that the composition of the microemulsion had a greater impact on the papp of cornea than on the papp of the other tissues the structure of the different membranes is probably responsible for the observed differences in permeation pulmonary emulsions and to a far lesser extent microemulsions have been investigated as vehicles for pulmonary delivery by far, the most widely studied systems are those containing fluorocarbon oil and are stabilized by a predominately fluorinated surfactant fluorocarbon oils are of pharmaceutical interest because of their biological inertness and their high and unique ability to dissolve gas, which means they can support the exchange of the respiratory gases in the lungs in addition, a fluorocarbon oil, namely perfluorooctylbromide, is in phase iiiii clinical trials in the united states, for the treatment of acute respiratory distress by liquid ventilation it should be noted that enlarge hydrocarbon surfactants are ineffective solubilizers in fluorocarbonbased systems instead, fluorocarbon surfactants are required to date, fluorocarbonbased microemulsions have been gangrene after penicillin investigated for use as oilinwater systems for in vivo oxygen delivery blood substitutes, targeted systems for diagnosis and therapy, and waterinfluorocarbon systems for pulmonary drug delivery waterinperfluorooctylbromide microemulsions have been shown to deliver homogeneous and reproducible doses of a tracer caffeine using metereddose inhalers pmdi pressurized with hydrofluoroalkanes hfas lecithinbased reverse microemulsions have also been investigated as a means of pulmonary drug delivery in these studies, dimethylethyleneglycol dmeg and hexane were used as models for the propellants, dimethyl ether dme and propane respectively a combination of equilibrium analysis and component diffusion rate determination by pulsedfield gradient [pfgjnmr and iodine solubilization experiments were used to confirm the formation of a microemulsion water soluble solutes, including selected peptides and fluorescently labeled poly a,[nhydroxyethyl d,laspartamide] were dissolved in the microemulsions in a lecithin and waterdependent manner experiments with dme lecithin demonstrated microemulsion characteristics similar to those in the model propellant and produced a droplet size and a fine particle fraction suitable for pulmonary drug delivery patel et aluo have prepared waterinhydrofluorocarbon specifically a microemulsions using a combination of fluorinated polyoxyethylene ether surfactants and a short chain hydrocarbon alcohol such as ethanol in the absence of a hydrocarbon alcohol, only cosolvent systems, but not microemulsions, were formed due to the high molecular weight of the gangrene after penicillin fluorocarbon surfactant, large concentrations of fluorocarbon surfactant are required to solubilize relatively small amounts of water compared with comparable hydrocarbonbased surfactants this has obvious implications for the pharmaceutical application of such systems to date, very little on the potential of oilinwater microemulsions for pulmonary drug delivery has been investigated, yet they are attractive vehicles because of their ability to solubilize high amounts of drug antibacterials aladham et al demonstrated that microemulsion formulations have a significant antimicrobial action against planktonic populations of both pseudomonas aeruginosa and staphylococcus aureus ie greater than a log cycle loss in viability over a period as short as s transmission electron microscopy studies indicated that this activity may in part be due to significant losses in outer membrane structural integrity nevertheless, these results have implications for the potential use of microemulsions as antimicrobial agents against this normally intransigent microorganism more recently, the same group have determined the antibiofilm activity of an oilinwater microemulsion, prepared from wt tween , wt pentanol and wt ethyl oleate, by incubating the microemulsion with an established biofilm culture of ps aeruginosa pa for a period of hrs the planktonic mic of sodium pyrithione and the planktonic and biofilm mics of cetrimide were used as positive controls and a biofilm was exposed to a volume gangrene after penicillin of normal sterile saline as a treatment negative control the results showed that exposure to the microemulsion resulted in a three logcycle reduction in biofilm viability, as compared to a one longcycle reduction in viability observed with the positive control treatments, suggesting that microemulsions are highly effective antibiofilm agents conclusion as can be seen, microemulsions are attractive drug delivery vehicles that offer much scope for improving drug delivery although microemulsions have been seriously studied as a delivery vehicle in the last years, there are few microemulsion products currently on the market comparing microemulsions with vesicular drug delivery systems, it is pertinent to note that it took years before vesicles were commercially exploited as drug delivery vehicles, and this was with the immense research effort expended in their study microemulsions have by contrast been much less widely studied it is only a matter of time before more microemulsionbased formulations appear on the market references aboofazeli r, mortazavi sa and khoshnevis p in vitro release study of sodium salicylate from lecithin based phospholipid microemulsions iran } pharm res aboofazeli r, pateln, thomas m and lawrence mj investigations into the formation and characterization of phospholipid microemulsions pseudoternary phase diagrams of systems containing waterlecithinalcohol and oil � the influence of oil int j pharm agatonovickustrin s and gangrene after penicillin alany rg role of genetic algorithms and artificial neural networks in predicting the phase behavior of colloidal delivery systems pharm res agatonovickustrin s, glass bd, wisch mh and alany rg prediction of a stable microemulsion formulation for the oral delivery of a combination of antitubercular drugs using ann methodology pharm res agrawal gp, juneja m, agrawal s, jain sk and pancholi ss preparation and characterization of reverse micelle based organogels of piroxicam pharmazie aladham isi, khalil e, alhmoud nd, kierans m and collier pj microemulsions are membraneactive, antimicrobial, selfpreserving systems j appl microbiol aladham isi, alhmoud nd, khalil e, kierans m and collier pj microemulsions are highly effective antibiofilm agents lett appl microbiol alany rg, agatonovickustrin s, rades t and tucker ig use of artificial neural networks to predict quaternery phase systems from limited experimental data pharm biomed anal alvarezfigueroa mj and blancomendez j transdermal delivery of methotrexate iontophoretic delivery from hydrogels and passive delivery from microemulsions int} pharm amselem s and friedman d submicron emulsions in drug targeting and delivery benita s eds harwood academic amsterdam anselem s, beilin m and garty n submicron emulsion as ocular delivery system for adaprolol maleate, a soft bblocker pharm res suppls angelico r, ceglie a, colafemmina g, lopez f, murgia s, olsson u and palazzo gangrene after penicillin g biocompatible lecithin organogels structure and phase equilibria langmuir arevalo mi, escribano e, calpena a, domenech j and queralt j rapid skin anesthesia using a new topical amethocaine formulation a preclinical study anesth anal atay nz and robinson bh kinetic studies of metal ion complexation in glycerol inoil microemulsions langmuir attama aa, nzekwe it, nnamani po, adikwu mu and onugu co the use of solid selfemulsifying systems in the delivery of diclofenac int j pharm attwood d microemulsions, in colloidal drug delivery systems kreuter j ed dekker new york attwood d, currie lrj and elworthy ph studies of solubilized micellar solutions phase studies and particlesize analysis of solutions formed with nonionic surfactants j coll interf sci aviv h, friedman d, barilan a and vered m submicron emulsions as ocular drug delivery vehicles us patent bagwe rp, kanicky jr, palla bj, patanjali pk and shah do improved drug delivery using microemulsions rationale, recent progress, and new horizons crit rev ther drug becker md, kruse fe, azzam l, nobiling r, reichling j and volcker he in vivo significance of icam dependent leukocyte adhesion in early corneal angiogenesis invest ophthalmol vis sci beilin m, barilan a and amselem s ocular retention time of submicron emulsion sme and the miotic response to pilocarpine delivered in sme invest gangrene after penicillin ophthalmol vis sci s bello m, colangelo d, gasco mr, maranetto f, morel s, podio v, turco gl and viano i pertechnetate release from a water oil microemulsion and an aqueoussolution after subcutaneous injection in rabbits ] pharm pharmacol benita s and levy my submicron emulsions as colloidal drug carriers for intravenous administration � comprehensive physicochemical characterization j pharm sci bhargava hn, narurkar a and lieb lm using microemulsions for drug delivery pharmaceut technol brime b, moreno ma, frutos g, ballesteros mp and frutos p amphotericin � in oilwater lecithinbased microemulsions formulation and toxicity evaluation j pharm sci brime b, molero g, frutos p and frutos g comparative therapeutic efficacy of a novel lyophilized amphotericin � lecithinbased oilwater microemulsion and deoxycholateamphotericin � in immunocompetent and neutropenic mice infected with candida albicans eur j pharm sci butz n, porte c, courrier hm, krafft mp and vandamme tf reverse water influorocarbon emulsions for use in pressurized metereddose inhalers containing hydrofluoroalkane propellants int} pharm calvo p, alonso mj and vilajato j comparative in vitro evaluation of several colloidal systems, nanoparticles, nanocapsules, and nanoemulsions, as ocular drug carriers j pharm sci carli f, chiellini ee, bellich b, macchiavelli s and cadelli g ubidecarenone nanoemulsified composite systems int j pharm castro d, moreno ma and lastres jl gangrene after penicillin firstderivative spectrophotometric and lc determination of nifedipine in brij based oilwateroil multiple microemulsions on stability studies j pharm biomed anal ceschel gc, maffei p, moretti mdl, peana at and demontis s in vitro permeation through porcine buccal mucosa of salvia sclarea l essential oil from topical formulations stp pharm sci chantrapornchai w, clydesdale fm and mcclements dj influence of relative refractive index on optical properties of emulsions food res int chen h, chang x, weng t, zhao x, gao z, yang y, xu h and yang x a study of microemulsion systems for transdermal delivery of triptolide} control rel chevalier y and zemb t the structure of micelles and microemulsions rep prog phys chu lw, hsiue gh and lin in ultrafine batio powders synthesized by inverse microemulsion processing and their microwave dielectric properties, am ceram soc constantinides pp lipid microemulsions for improving drug dissolution and oral absorption physical and biopharmaceutical aspects pharm res constantinides pp, scalart jp, marcello lj, marks g, ellens h and smith pl formulation and intestinal absorption enhancement evaluation of wateriinoil microemulsions incorporating mediumchain glycerides pharm res constantinides pp, lancaster cm, marcello j, chiosone dc, orner d, hidalgo i, smith pl, sarkahian ab, yiv sh and owen aj enhanced intestinal absorption of an rgd peptide from waterinoil nanoemulsions of different gangrene after penicillin composition and size j control rel von corswant c, thorean p and engstrom s triglyceridebased microemulsion for intravenous administration of sparingly soluble substances pharm sci courrier hm, butz n and vandamme tf pulmonary drug delivery systems recent developments and prospects crit rev ther drug courrier ha, vandamme tf and krafft mp reverse waterinfluorocarbon emulsions and microemulsions obtained with a fluorinated surfactant coll surf physicochem eng asp cui z, fountain w, clark m, jay m and mumper rj novel ethanolin fluorocarbon microemulsions for topical genetic immunization pharm res dalmora med and oliveira ag inclusion complex of piroxicam with f cyclodextrin and incorporation in hexadecyltrmethylammonium bromide based microemulsion int j pharm dalmora me, dalmora sl and oliveira ag inclusion complex of piroxicam with scyclodextrin and incorporation in cationic microemulsion in vitro drug release and in vivo topical antiinflammatory effect int f pharm danielsson i and lindman � the definition of a microemulsion coll surf dcruz oj and uckun mh gelmicroemulsions as vaginal spermicides and intravaginal drug delivery vehicles contraception dcruz oj and uckun fm preclinical safety evaluation of novel nucleoside analoguebased dualfunction microbicides whi and whi j antimicrob chem dcruz oj and uckun fm contraceptive activity of a spermicidal aryl phosphate derivative of bromomethoxyzidovudine compound whi in rabbits fertil sterio djordjevic l, primorac m and gangrene after penicillin stupar m in vitro release of diclofenac diethylamine from caprylocaproyl macrogolglycerides based microemulsions int j pharm eccleston j microemulsions, in encyclopedia of pharmaceutical technology, vol , swarbrick j and boylan jc eds marcel dekker new york elaasser ms polymeric dispersions asua jm ed kluwer academic publications the netherlands elbaz e, zeevi a, klang s and benita s positively charged submicron emulsions, a new type of colloidal drug carrier int f pharm rr escribano e, calpena ac, queralt j, obach r and domenech j assessment of diclofenac permeation with different formulations antiinflammatory study of a selected formula eur f pharm sci evitts dp, olejnik o, musson dg and bilgood am aqueous ophtalmic microemulsions of tepoxalin european patent application al faldt p and bergenstahl � fat encapsulation in spray dried food powders assoc offic anal chem fang j, wang j, ng sc, chew ch and gan lm ultrafine zirconia powders via microemulsion processing route nanostruct mater feng l and dexi ll circulating emulsions oilinwater as carriers for lipophilic drugs pharm res fialho sl and da silvacunha a new vehicle based on a microemulsion for topical ocular administration of dexamethasone clin exp ophthalmol florence at and attwood d physicochemical pharmacy rd ed, macmilliam press, ltd forgiarini a, esquena j, gonzalez � and solans � formation of gangrene after penicillin nano emulsions by lowenergy emulsification methods at constant temperature langmuir gallarate m, gasco mr and trotta m influence of octanoic acid on membrane permeability of timolol from solutions and from microemulsions acta pharm technol gallarate m, gasco mr, trotta m, chetoni p and saettone mf preparation and evaluation in vitro of solutions and ow microemulsions containing levobunolol as ionpair int j pharm garty n and lusky m pilocarpine in submicron emulsion formulation for treatment of ocular hypertension a phase ii clinical trial invest ophth vis sci gasco mr, pattarino f and lattanzi if longacting delivery systems for peptides reduced plasma testosterone levels in male rats after a single injection int j pharm gershanik t and benita s selfdispersing lipid formulations for improving oral absorption of lipophilic drugs eur j pharm biopharm getie m, wohlrab j and neubert rrh dermal delivery of desmopressin acetate using colloidal carrier systems j pharm pharmacol groves mj and de galindez da the selfemulsifying action of mixed surfactants in oil acta pharm suet gulsen d and chauhan a dispersion of microemulsion drops in ���� hydro gel a potential ophthalmic drug delivery vehicle int f pharm gupta rr, jain sk and varshney m aot waterinoil microemulsions as a penetration enhancer in transdermal drug delivery of fluorouracil coll surf biointerf haering gangrene after penicillin g and luisi pl hydrocarbon gels from waterinoil microemulsions j phys chem hasse a and kiepert s development and characterization of microemulsions for ocular application eur f pharm biopharm he l, wang g and zhang q an alternative paclitaxel microemulsion formulation hypersensitivity evaluation and pharmacokinetic profile int f pharm hellweg t phase structures of microemulsions curr opin coll interf sci hu z, tawa r, konishi t, shibata n and takada � a novel emulsifier, labrasol, enhances gastrointestinal absorption of gentamicin life sci husband fa, garrood mj, mackie ar, burnett gr and wilde pj adsorbed protein secondary and tertiary structures by circular dichroism and infrared spectroscopy with refractive index matched emulsions agri food chem hwang sr, lim sj, park js and kim ck phospholipidbased microemulsion formulation of alhransretinoic acid for parenteral administration int ] pharm iek ac, eebi nc, tirnaksiz f and tay a a lecithinbased microemulsion of rh insulin with aprotinin for oral administration investigation of hypoglycemic effects in nondiabetic and stz induced diabetic rats int j pharm imberg a and engstrom s an increased throughput method for determination of phase diagramsmethod development and validation coll surf physicochem eng asp itoh k, matsui s, tozuka y, oguchi t and yamamoto � improvement of physic ochemical properties of n part ii characterization of n gangrene after penicillin microemulsion and the enhanced oral absorption int} pharm izquierdo p, esquena j, tadros tf, dederen jc, feng j, garciacelma mj, azemar n and solans � phase behavior and nanoemulsion formation by the phase inversion temperature method langmuir izquierdo p, feng j, esquena j, tadros tf, dederen jc, garcia mj, azemar n and solans � the influence of surfactant mixing ratio on nanoemulsion formation by the pit method j coll interf sci jaitely v, sakthivel t, magee g and florence at formulation of oil in oil emulsions potential drug reservoirs for slow release j drug del sci tech joussen am, rohrschneider k, reichling j, kirchhof � and kruse fe treatment of corneal neovascularization with dietary isoavonoids and flavonoids exp eye res junping wj, takayama k, nagai t and maitani y pharmacokinetics and antitumor effects of vincristine carried by microemulsions composed of peglipid, oleic acid, vitamin e and cholesterol int} pharm jurkovic p, sentjurc m, gasperlin m, kristl j and pecar s skin protection against ultraviolet induced free radicals with ascorbyl palmitate in microemulsions eur j pharm biopharm kanga bk, chonb sk, kimb sh, jeongc sy, kimc ms, choc sh, leec hb and khanga g controlled release of paclitaxel from microemulsion containing plga and evaluation of antitumor activity in vitro and in vivo int} gangrene after penicillin pharm kang ls, jun hw and mccall jw physicochemical studies of lidocainementhol binary systems for enhanced membrane transport int j pharm kantaria s, rees gd and lawrence mj gelatinstabilised microemulsionbased organogels rheology and application in iontophoretic transdermal drug delivery j control rel kantaria s, rees gd and lawrence mj formulation of electrically conducting microemulsionbased organogels int ] pharm kawakami k, yoshikawa t, moroto y, kanaoka e, takahashi k, nishihara y and masuda � a microemulsion formulation for enhanced absorption of poorly soluble drugs i prescription design j control rel kawakami k, yoshikawa t, hayashi t, nishihara y and masuda � b microemulsion formulation for enhanced absorption of poorly soluble drugs ii in vivo study j control rel ke wt, lin sy, ho ho and sheu mt physical characterizations of microemulsion systems using tocopheryl polyethylene glycol succinate tpgs as a surfactant for the oral delivery of protein drugs j control rel khoo sm, porter cjh and charman wn the formulation of halofantrine as either nonsolubilising peg or solubilising lipid based solid dispersions physical, stability and absolute bioavailability assessment int} pharm khoo sm, shackleford dm, porter cjh, edwards ga and charman wn intestinal lymphatic transport of halofantrine occurs after oral administration of a unitdose lipidbased formulation to fasted dogs pharm res khoshenvis p, mortazavi sa, gangrene after penicillin lawrence mj and aboofazeli r in vitro release of sodium salcylate from waterinoil microemulsions j pharm pharmacol s kim ck, ryuu sa, park km, lim sj and hwang sj preparation and physic ochemical characterization of phase inverted wateroil microemulsion containing cyclosporin a int j pharm kim ck, shin hj, yang sg, kim jh and oh yk a onceaday oral dosing regimen of cyclosporin a combined therapy of cyclosporin cymbalta is there generic a premicroemulsion concentrates and enteric coated solidstate premicroemulsion concentrates pharm res kim ck, cho yj and gao zg b preparation and evaluation of biphenyl dimethyl dicarboxylate microemulsions for oral delivery j control rel kim sk, lee eh, vaishali b, lee s, lee yk, kim cy, moon ht and byun y tri caprylin microemulsion for oral delivery of low molecular weight heparin conjugates j control rel klang sh, baszkin a and benita s the stability of piroxicam incorporated in a positively charged submicron emulsion for ocular administration int } pharm kraeling mek and ritschel wa development of a colonic release capsule dosage form and the absorption of insulin meth find exp clin pharmacol krafft mp, chittofrati a and riess jg emulsions and microemulsions with a fluorocarbon phase curr opin coll interf sci kreilgaard m influence of microemulsions on cutaneous drug delivery adv drug del rev ss gangrene after penicillin lam ac and schechter rs the theory of diffusion in microemulsion j coll interf sci lawrence mj surfactant systems microemulsions and vesicles as vehicles for drug delivery eur j drug metab pharmacokinet lawrence mj microemulsions as drug delivery vehicles curr opin coll inter sci lawrence mj and rees gd microemulsionbased media as novel drug delivery systems adv drug del rev lee mj, lee mh and shim ck inverse targeting of drugs to reticuloendothelial systemrich organs by epid microemulsion emulsified with poloxamer int j pharm lee jm, park km, lim sj, lee mk and kim ck microemulsion formulation of clonixic acid solubility enhancement and pain reduction j pharm pharmacol lee pj, langer r and shastri vp novel microemulsion enhancer formulation for simultaneous transdermal delivery of hydrophilic and hydrophobic drugs pharm res lettow js, lancaster tm, glinka cj and ying jy smallangle neutron scattering and theoretical investigation of polyethylene oxidepolypropylene oxide polyethylene oxide stabilized oilinwater microemulsions langmuir levy my and benita s design and characterization of a submicronized ow emulsion of diazepam for parenteral use int ] pharm levy my and benita s shortterm and longterm stability assessment of a new injectable diazepam submicron emulsion } parent sci tech li l, nandi i and kim kh development of an ethyl lauratebased microemulsion for rapidonset gangrene after penicillin intranasal delivery of diazepam int j pharm lladser m, medrano � and arancibia a the use of supports in the lyophilization of oilinwater emulsions j pharm pharmacol lopez f, venditti f, ambrosone l, colafemmina g, ceglie a and palazzo g gelatin microemulsionbased gels with the cationic surfactant cetyltrimethylammo nium bromide a selfdiffusion and conductivity study langmuir lu yy, xia q, xia y ma qh and gu n studies on the phase behaviors of drug loading microemulsions acta physicochimica sinica lundberg bb a submicron lipid emulsion coated with amphipathic polyethylene glycol for parenteral administration of paclitaxel taxol } pharm pharmacol lyons ��, charman wn, miller r and porter cjh factors limiting the oral bioavailability of nacetylglucosaminylnacetylmuramyl dipeptide gmdp and enhancement of absorption in rats by delivery in a waterinoil microemulsion int } pharm malcolmson � and lawrence mj a comparison of the incorporation of model steroids into nonionic micellar and microemulsion systems j pharm pharmacol malcolmson � and lawrence mj threecomponent nonionic oilinwater microemulsions using polyoxyethylene ether surfactants coll surf � biointerf malcolmson c, satra c, kantaria s, sidhu a and lawrence mj effect of oil on the level of solubilization of testosterone propionate into nonionic oilinwater microemulsions j pharm sci malcolmson c, barlow dj and lawrence mj lightscattering studies of testosterone enanthate containing gangrene after penicillin soybean oilcisi �� water oilinwater microemulsions } pharm sci mei z, chen h, weng t, yang y and yang x solid lipid nanoparticle and microemulsions for topical delivery of triptolide eur j pharm biopharm melamed s, kurtz s, greenbaum a, haves jf, neumann r and garty n adaprolol maleate in submicron emulsion, a novel soft blocking agent, is safe and effective in human studies invest ophthalmol vis sci moreno ma, ballesteros mp and frutos p lecithinbased oilinwater microemulsions for parenteral use pseudoternary phase diagrams, characterization and toxicity studies } pharm sci mistry vv, hassan hn and robison dj effect of lactose and protein on the microstructure of dried milk food struct myers sl and shively ml preparation and characterization of emulsifiable glasses oilinwater and waterinoilinwater emulsions, ] coll interf sci muchtar s, almong s, torraca mt, saettone mf and benita s a submicron emulsion as ocular vehicle for delta tetrahydrocannabinol effect on intraocular pressure in rabbits ophtalmic res muchtar s, abdulrazik m, benita s ex vivo permeation study of indomethacin from a submicron emulsion through albino rabbit cornea j control rel nakajima h, tomomasa s and okabe m preparation of nanoemulsions, in proceedings of first emulsion conference, paris, eds paris, vol nazzal s, guven n, reddy ik and khan ma preparation and characterization gangrene after penicillin of coenzyme qloeudragit solid dispersion drug dev ind pharm naveh n, muchtar s and benita s pilocarpine incorporated into a submicron emulsion vehicle causes an unexpectedly prolonged ocular hypotensive effect in rabbits ocul pharmacol newton m, petersson j, podczeck f, clarke a and booth s the influence of formulation variables on the properties of pellets containing a selfemulsifying mixture j pharm sci nyqvistmayer aa, brodin af, frank sg phase distribution studies on an oil water emulsion based on a eutectic mixture of lidocaine and prilocaine as the dispersed phase j pharm sci osborne dw, ward aj and oneill kj microemulsions as topical drug delivery vehicles in vitro transdermal studies of a model hydroplilic drug j pharm pharmacol paolino d, ventura ca, nistico s, puglisi g and fresta m lecithin microemulsions for the topical administration of ketoprofen percutaneous adsorption through human skin and in vivo human skin tolerability int f pharm park km and kim ck preparation and evaluation of flurbiprofenloaded microemulsion for parenteral delivery int j pharm park km, lee mk, hwang kj and kim ck phospholipidbased microemulsions of flurbiprofen by the spontaneous emulsification process int j pharm patel p, marlow m and lawrence mj formation of fluorinated nonionic surfactant microemulsions in hydrofluorocarbon a hfc a co interf sci patil p, joshi p gangrene after penicillin and paradkar a effect of formulation variables on preparation and evaluation of gelled selfemulsifying drug delivery system sedds of ketoprofen aaps pharm sci tech article pattarino f, marengo e, gasco mr and carpignano r experimentaldesign and partial leastsquares in the study of complexmixtures � microemulsions as drug carriers int j pharm pedersen gp, faldt p, bergenstahl � and kristensen hg solid state characterisation of a dry emulsion a potential drug delivery system int j pharm podlogar f, gasperlin m, tomsic m, jamnik a and bester rogac m structural characterisation of watertween imwitor isopropyl myristate microemulsions using different experimental methods int j pharm porter cjh, kaukonen am, boyd bj, edwards ga and charman wn susceptibility to lipasemediated digestion reduces the oral bioavailability of danazol after administration as a mediumchain lipidbased microemulsion formulation pharm res pouton cw formulation of selfemulsifying drug delivery systems adv drug del rev priano l, albani g, brioschi a, calderoni s, lopiano l, rizzone m, cavalli r, gasco mr, scaglione f, fraschini f, bergamasco � and mauro a transdermal apomorphine permeation from microemulsions a new treatment in parkinsons disease movement disorders quellet � and eicke hf mutual gelation of gelatin and waterinoil microemulsions chimia richardson cj, mbanefo a, aboofazeli r, lawrence mj and barlow dj prediction of phase behavior in gangrene after penicillin microemulsion systems using artificial neural networks coll interf sci richter a and steigertrippi � untersuchungen iiber die zerstaubungstrocknung von emulgierten arzneizubereitungen pharm acta helv richter t and keipert s in vitro permeation studies comparing bovine nasal mucosa, porcine cornea and artificial membrane androstenedione in microemulsions and their components eur j pharm biopharm ritschel wa microemulsions for improved peptide absorption from the gastrointestinaltract meth findings exp clin pharmacol ross ea, savage ka, utley lj and tebbett ir insect repellant interactions sunscreens enhance deetw, �diethylmtoluamide absorption drug metabolism dispos rowe rc, sheskey pj and weller pj pharmaceutical excipients handbook, pharmaceutical press and american pharmaceutical association, dundee santiago rm, fialho sl and silvacunha a design and characterization of an oral delivery system for insulin administration stp pharma sci santos magalhaes ns, cave g, seiller m and benita s the stability and in vitro, release kinetics of a clofibride emulsion int j pharm satra c, thomas m and lawrence mj formulating oilinwater microemulsions for pulmonary drug delivery, in drug delivery to the lungs iv, the aerosol society bristol, london scherlund m, malmsten m, holmqvist p and brodin a thermosetting microemulsions and mixed micellar solutions as drug delivery systems for periodontal anesthesia int} pharm schwab m and stuhn � relaxation phenomena and development of structure in a physically gangrene after penicillin crosslinked nonionic microemulsion studied by photon correlation spectroscopy and small angle xray scattering chem phys schulman jh, stoechenius w and prince lm mechanism of formation and structure of microemulsions by electron microscopy j phys chem schurtenberger p and cavaco � the static and dynamic structure factor of polymerlike lecithin reverse micelles } physique ii siebenbrodt i and keipert s poloxamersystems as potential ophthalmic microemulsions eur j pharm biopharm sha x, yan g, wu y, li j and fang x effect of selfmicroemulsifying drug delivery systems containing labrasol on tight junctions in caco cells eur ] pharm sci shiokawa t, hattori y, kawano k, ohguchi y, kawakami ii, toma � and maitani y effect of polyethylene glycol linker chain length of folatelinked microemulsions loading aclacinomycin a on targeting ability and antitumor effect in vitro and in vivo clin cancer res shukla a, krause a and neubert rrh microemulsions as colloidal vehicle systems for dermal drug delivery part iv investigation of microemulsion systems based on a eutectic mixture of lidocaine and prilocaine as the colloidal phase by dynamic light scattering j pharm pharmacol siebenbrodt i and keipert s poloxamersystems as potential ophtalmic microemulsions eur j pharm biopharm sinn � when jelly gets the blues � audible sound generation with gels and its origin } noncryst gangrene after penicillin sol sintov ac and shapiro l new microemulsion vehicle facilitates percutaneous penetration in vitro and cutaneous drug bioavailability in vivo j control rel solans c, esquena j, forgiarini a, uson n, morales d, izquierdo p, azemar n and garcia mj adsorption and aggregation of surfactants in solution mittal kl and shah do, eds marcel dekker new york sommerville ml, cain jb, johnson cs and hickey aj lecithin inverse microemulsions for the pulmonary delivery of polar compounds utilizing dimethylether and propane as propellants pharmaceut dev technol sommerville ml, johnson cs, cain jb, rypacek f and hickey aj lecithin microemulsions in dimethyl ether and propane for the generation of pharmaceutical aerosols containing polar solutes pharmaceut dev technol strickley rg solubilizing excipients in oral and injectable formulations pharm res tadros tf, izquierdo p, esquena j and solans � formation and stability of nanoemulsions adv coll interf sci taha mo, alghazawi m, abuamara h and khalil e development of quantitative structureproperty relationship models for pseudoternary microemulsions formulated with nonionic surfactants and cosurfactants application of data mining and molecular modeling eur ] pharm sci taha mo, abuamara h, alghazawi m and khalil e qspr modeling of pseudoternary microemulsions formulated employing lecithin surfactants application of data mining, molecular and statistical modeling int} pharm tenjarla s microemulsions an overview gangrene after penicillin and pharmaceutical applications crit rev ther drug carr sys ugelstadt j, elaassar ms and vanderhoff jw emulsion polymerization � initiation of polymerization in monomer droplets} polym sci vandamme tf microemulsions as ocular drug delivery systems recent developments and future challenges prog retin eye res valduga cj, fernandes dc, lo prete ac, azevedo, chm, rodrigues dg and maranhao rc use of a cholesterolrich microemulsion that binds to lowdensity lipoprotein receptors as vehicle for etoposide j pharm pharmacol valenta � and schultz � influence of carrageenan on the rheology and skin permeation of microemulsion formulations } control rel varshney m, morey ��, shah do, flint ja, moudgil bm, seubert cn and dennis dm pluronic microemulsions as nanoreservoirs for extraction of bupivacaine from normal saline j am chem soc vyas sp, jain cp, kaushik a and dixit vk preparation and characterisation of griseofulvin dry emulsion pharmazie wang j, maitani y and takayma � antitumor effects and pharmacokinetics of aclacinomycin a carried by injectable emulsions composed of vitamin e, cholesterol and peglipid j pharm sci wang j, chong pp, ng sc and gan lm microemulsion processing of manganese zinc ferrites mat lett warisnoicharoen w, lansley ab and lawrence mj nonionic oilinwater microemulsions the effect of oil type on phase behaviour int f pharm watnasirichaikul s, rades t, gangrene after penicillin tucker ig and da vies nm in vitro release and oral bioactivity of insulin in diabetic rats using nanocapsules,dispersed in biocompatible microemulsion ] pharm pharmacol xu qy, nakajima m, nabetani h, ichikawa s and liu xq factors affecting the properties of ethanolinoil emulsions food sci tech res yamamoto a, taniguchi t, rikyuu k, tsuji t, fujita t, murakami m and muranishi s effects of various protease inhibitors on the intestinal absorption and degradation of insulin in rats pharm res yang s, gursoy rn, lambert g and benita s enhanced oral absorption of paclitaxel in a novel selfmicroemulsifying drug delivery system with or without concomitant use of pglycoprotein inhibitors pharm res zhang zq and lu � advances in microemulsions as a vehicle of drug delivery system chin j pharm zhang l, sun x, xiang d and zhang zr a formulation and physicochemical characterization of norcantharidin microemulsion containing lecithinbased surfactants j drug del sci tech zhang q, jiang x, jiang w, lu, w, su l and shi z b preparation of nimodipine loaded microemulsion for intranasal delivery and evaluation on the targeting efficiency to the brain int j pharm this page is intentionally left blank lipoproteins as pharmaceutical carriers suwen liu, shining wang and d robert lu introduction large protein structures in nanometer range gangrene after penicillin may be utilized as pharmaceutical carriers of drugs and dna for targeted and other specialized delivery in biological systems lipoproteins are such structures which function as natural biological carriers and transport various types of lipids in blood circulation there are many studies suggesting that lipoproteins can serve as efficient carriers for anticancer drugs, gene or other type of compounds previous results showed that hydrophobic cytotoxic drugs could be incorporated into lipoproteins, without changing the integrity of native lipoprotein structure lipoproteins as drug carriers offer several advantages firstly, they are endogenous components and do not trigger immunological response they have a relatively long halflife in the circulation secondly, they have small particle size in the nanometer range, allowing the diffusion from vascular to extravascular compartments thirdly, lipoproteins can potentially serve as the carriers for targeted drug delivery through specific cellular receptors for example, low density lipoprotein ldldrug complexes may target cancer cells which, in many cases, have higher ldlreceptor expression than normal cells fourthly, the lipid core of lipoprotein provides a suitable compartment for carrying hydrophobic drugs as a result of these advantages, lipoproteins have received wide attentions in recent years in the development of drugtargeting strategies to use them as specialized delivery vehicles this review intends to provide an overview of the gangrene after penicillin development and the specialized utilization of lipoproteins for drug delivery purpose after briefly introducing the structure and the basic biological functions of lipoproteins, we will focus on four classes of lipoproteins, namely, chylomicron, very lowdensity lipoprotein vldl, lowdensity lipoprotein ldl, and highdensity lipoprotein hdl, as the carriers for various drug compounds cholesterolrich emulsions lde and artificial lipoproteins as drug carriers will also be discussed the structure of lipoproteins lipoproteins, as implied by their names, are biological proteinlipid complexes lipoproteins serve the functions of carrying hydrophobic substances in blood circulation and transporting them to various biological sites through the proteinreceptor interactions, the size of lipoproteins is in the nanometer range and they have a spherical shape with complex physicochemical properties figure illustrates the general structure of lipoprotein the hydrophobic core contains waterinsoluble substances and is surrounded by a polar shell the polar shell consists of phospholipids, unesterified cholesterol and different types of apolipoproteins, which bind to various cellular receptors for specific biological functions therefore, based on their physicochemical properties, lipoproteins are nanoemulsions with targeting functions provided by the apolipoproteins owing to the unique structure of lipoproteins, they can serve a twomode function of solubilizing hydrophobic substances, including triglycerides and cholesteryl esters, within the nanoemulsion core and allow themselves to float in blood circulation lipoproteins gangrene after penicillin can be classified into five major classes, based on their densities from gradient ultracentrifugation experiments the lipoprotein classification includes chylomicron, very lowdensity lipoprotein vldl, intermediatedensity lipoprotein idl, lowdensity lipoprotein ldl, and highdensity lipoprotein hdl these classes of lipoproteins have different sizes, different protein to lipid ratios and different types of apolipoproteins in general, chylomicrons act on transporting dietary triacylglycerols and cholesterol to the adipose tissue and liver, following the absorption of dietary hydrophobic substances from the intestines very fig general structure of lipoproteins table physicochemical properties of lipoproteins lipoprotein transport route size nm protein total lipids chylomicron intestines to liver vldl liver to tissues idl liver to tissues ldl liver to tissues hdl tissues to liver low density lipoprotein, intermediate density lipoprotein and low density lipoprotein work at different stages to transport triacylglycerols and cholesterol from the liver to various tissues high density lipoprotein brings endogenous cholesterol from the tissues back to the liver the general physicochemical properties of lipoproteins can be seen in table chylomicron as pharmaceutical carrier chylomicrons are assembled in the intestine from the absorbed dietary lipids and transported by lymphatic system although most of the drugs administered orally are absorbed directly into the portal blood to reach the systemic circulation, an alternative absorption route through the intestinal lymphatics may gangrene after penicillin be available for hydrophobic drugs it is estimated that a high hydrophobicity log ow partition coefficient of drug molecules is required for intestinal lymphatic transport chylomicrons can thus potentially serve as an important natural carrier for hydrophobic drugs to transport through lymphatic system it is known that targeted drug delivery through the lymphatics is important for antiviral drug molecules for the protection of b and tlymphocytes, which maintain relatively higher concentrations through the lymphatics than the systemic circulation chylomicrons have a much larger size than other lipoproteins, and thus can carry more drug molecules from the absorption site with the presence of food, chylomicrons are the predominant lipoprotein produced by the small intestine to carry dietary lipids efficiently because of its large size various types of bioactive molecules have been incorporated into reconstituted chylomicron structure for delivery purposes in gene delivery, hara et al, developed reconstituted chylomicron which incorporated a hydrophobic dna complex and used it as an in vivo gene transfer vector they found that the dnaincorporated chylomicrons induced a high gene expression in mouse liver after the reconstituted chylomicron was administered through portal vain injection furthermore, it was also reported that artificial, proteinfree lipid emulsions could be utilized to model the metabolism of lymph chylomicron in rats, not only in gangrene after penicillin the initial partial hydrolysis by lipoprotein lipase, but also in the delivery of a remnantlike particle to the liver as a targeted therapeutic approach to hepatitis b, antiviral iododeo cyuridine was incorporated into recombinant chylomicrons, resulting in the drug molecules being selectively targeted to the liver parenchymal cells it has been suggested that chylomicron can serve as a special carrier for liver cell targeting due to the targetability, this approach could be further developed as an effective therapy for hepatitis � patients vldl as pharmaceutical carrier vldl particles have a size range of nm they are assembled in the endoplasmic reticulum er and matured in golgi apparatus of hepatocytes before secretion after entering into the plasma, vldl particles are catabolized by a series of biochemical actions, including apolipoprotein exchange of apoci, apoc ii, apociii, and apoe lipolysis by triglyceride lipase and cellsurface receptor mediated uptake as lipolysis proceeds, vldl particles become smaller and are eventually converted to idl some of the idl particles are rapidly taken up by hepatocytes via a receptormediated mechanism while others undergo further hydrolysis before being converted to ldl the catabolism route of vldl suggests the possibility of using vldl as a drug carrier for targeted delivery apoe is a protein ligand present on the surface of vldl and gangrene after penicillin it is well known that the receptor of apoe is overexpressed on some types of cancer cells therefore, vldl can potentially serve as an antineoplastic drug carrier as a drug carrier, vldl is an interesting candidate because it contains a relatively small amount of proteins about protein and a large amount of triglycerides about within the emulsion core which can be used to solubilize hydrophobic substances sufficiently by mimicking the compositions and structure of vldl, shawer et al developed a vldlresembling phospholipid nanoemulsion system that carried a new antitumor boron compound for targeted delivery to cancer cells the nanoemulsion demonstrated sufficient capability to solubilize the hydrophobic compound the structure of the phospholipid nanoemulsion was verified based on the changes in the molecular surface area and the molecular volume of each component of the nanoemulsion when the particle size is changed from different size fractions if certain molecules are located at the core of nanoemulsion, their numbers per overall volume should not be changed when the particle size is increased if certain molecules are located at the surface of nanoemulsion, their numbers per overall volume should decrease when particle size is increased this is because the overall surface area decreases when particle size is increased similar to the natural lipoproteins, it was demonstrated that gangrene after penicillin phospholipid was predominately located at the surface and the hydrophobic substances, triolein and cholesteryl oleate, were mainly located in the core of the phospholipid nanoemulsion recently, a similar nanoemulsion formulation was used to encapsulated quantum dots qd as a new bioimaging carrier quantum dots qds are semiconductor nanocrystals that are emerging as unique fluorescence probes in biomedicine when manufactured, most of the quantum dots have organic ligand coating on their surface and are extremely hydrophobic the research goal was to encapsulate qds in phospholipid nanoemulsion and to examine the physical stability, size distribution and their interactions with cancer cells it was found that cdse qds can be efficiently encapsulated in the phospholipid nanoemulsion the qdencapsulated phospholipid nanoemulsion are stable and interact well with cultured cells to deliver the qds inside the cells for fluorescence imaging in other studies, it has been demonstrated that cytotoxic drugs such as fluorouracil fu, iododeoxyuridine iudr, doxorubicin dox, and vindesine can be effectively incorporated into vldl, and the resultant complexes showed effective cytotoxicity to human carcinoma cells ldl as pharmaceutical carrier ldl nm is not directly synthesized in human body instead, most of them are formed through the vldl pathway ldl is the major circulatory lipoprotein for the transport of cholesterol and cholesteryl esters, and it can gangrene after penicillin be internalized by cells via ldl receptormediated endocytosis the internalization process of ldl has been well characterized and the understanding of the mechanism can potentially help the designing of the drug targeting strategy through the ldl receptor fig the binding of dephosphorylated adaptor protein to the plasma membrane ldl binding �internalization �?drug release �?regulation fig ldl receptor pathway and targeted drug delivery initiates the formation of coated pits which are covered by the protein clathrin the receptors from the surrounding regions of the plasma membrane shift towards the binding site for internalization apolipoproteins including apo b and apo e are recognized and bound by the ldl receptor on the cell surface to form a complex which is internalized into the coated pits after internalization of the ldl, the coated pits are pinched off and within a very short time, they shed off their clathrin coating the internalized ldl particle is transferred to endocytotic vesicles or endosomes due to the acidic ph within the endosomes, ldl dissociates from its receptor this is followed by the fusion of the endosomes with lysosomes which contain hydrolases the protein component of ldl is broken into free amino acids, while the cholesteryl ester component is cleaved by lysosomal lipase the free cholesterol is released and incorporated gangrene after penicillin into the cell membrane excess cholesterol is reesterified by the action of acylcoacholesterol acyltransferase acat among various lipoproteins, ldl has been widely studied as a drug carrier for targeted and other specialized deliveries, because many types of cancer cells show elevated expression of ldl receptors than the corresponding normal cells comparing with chylomicron, vldl, and idl, ldl also has a longer serum half life of days, making it a desirable drug carrier low density lipoprotein was found to be suitable as carriers for cytotoxic drugs to target cancer cells ldl drug complexes can be formed through various processes without changing the lipoprotein integrity ldl as anticancer drug carriers doxorubicin dox is widely used in treating different tumors its main side effects are cadiotoxicity and multidrug resistance, especially during prolonged treatment in the patients ldl has been studied as a target carrier for dox in nude mice, bearing human hepatoma hepg cells both in vitro and in vivo studies indicated that when dox was incorporated into ldl, the multidrug resistance could be circumvented and the cardiotoxicity could be reduced as well kader and pater used vldl, ldl and hdl as carriers to deliver four cytotoxic drugs, fluorouracil fu, iododeoxyuridine iudr, doxorubicin dox and vindesine they found that significant drug loading was achieved in all gangrene after penicillin three classes of lipoproteins, consistent with the sizes and hydrophobicity of the drug experiments were carried out to examine the changes in drug cytotoxicity against hela cervical and mcf breast carcinoma cells, after the incorporation into lipoprotein the results demonstrated that vldldrug complex did not affect their ic on both hela and mcf cell lines, when compared with free drugs however, the ic values of ldl and hdl drug complexes were significantly lower compared with free drugs their studies further indicated that drugs were incorporated into lipoproteins without disrupting their integrity drugs remained in their stable forms inside lipoproteins and human ldl and hdl could be particularly useful in the delivery of antineoplastic drugs ldl as carriers for other types ofbioactive compounds although ldl has been widely studied as a carrier to deliver anticancer compounds, it may also be useful to deliver other types of bioactive compounds ldl may serve as a carrier for sitespecific delivery of drugs to atherosclerotic lesions when dexamethasone palmitate dp, a steroidal antiinflammatory drug, was incorporated in ldl, an inhibitory effect of this complex on foam cell formations was demonstrated the study indicated that ldl could potentially carry dp to atherosclerotic lesions fluorophorelabeled ldl was also used for optical imaging in tumors diagnosis for example, carbocyanine dyes can gangrene after penicillin be used as near infrared nir optical imaging probes with long wavelength absorption, high extinction coefficients and high fluorescence quantum yield in vitro confocal microscopic study and ex vivo lowtemperature fluorescent scanning demonstrated that carbocyninelabled ldl probes, dilldl, could be selectively delivered to bhepg tumor cells and the corresponding animal tumors via the ldl receptor pathway it was also proposed that dil is located and oriented in the phospholipid monolayer when it binds to ldl ldl for gene delivery ldl has also been investigated as gene delivery carriers comparing with viral genedelivery vectors and some other types of nonviral gene delivery vectors, the ldl system shows certain advantages in transfection efficiency and safety considerations several ldl based gene delivery systems have been reported kims group developed a terplex system which comprises ldl, lipidized polyl lysine and plasmid dna the complex had a diameter of about nm the studies showed high efficiency to deliver plasmid dna to smooth muscle cells and fibroblast cells in addition, a novel ldldna complex was formulated by khan et al ldl was cationized using carbodiimide and the modified lipoprotein complex significantly increased the dna binding capacity with improved stability the novel delivery system also demonstrated the ability to target cells through ldl receptor hdl as pharmaceutical carriers among gangrene after penicillin various lipoproteins, hdl has the smallest size with a diameter of nm it shares common structural characteristics with other lipoproteins however, its polar shell contributes more than of the total mass newly synthesized hdl hardly contains any cholesteryl ester molecules cholesteryl esters are gradually added to the particles by lecithin via enzymatic reaction cholesterol acyltransferase lcat, which is a kd glycoprotein associated with hdl the interaction of hdl with cells appears similar to that of ldl although the function of hdl in the human body is not welldefined, it generally transports excess cholesterol and cholesteryl esters from various tissue cells back to the liver comparing with other types of lipoproteins, small size and fast internalization by tumor cells are the major advantages of utilizing hdl for drug delivery and targeting hdl has mainly been utilized for the delivery of water insoluble anticancer drugs through the targeting function when the anticancer drug, taxol, was incorporated into hdl, stable complexes were formed and they were examined for cancercell targeting reconstituted hdl was explored as a drug carrier system for a lipophilic prodrug, iduoi the studies indicated that the lipophilic prodrug could be efficiently incorporated into reconstituted hdl particles this approach may also be useful to encapsulate other lipophilic derivatives of watersoluble drugs the utilization of gangrene after penicillin hdl for drug targeting may lead to a more effective therapy for infectious diseases, such as hepatitis b, since the hdldrug complexes were demonstrated to be selectively taken by parenchymal liver cells comparing with free drugs in cytotoxicity assays, the � values of hdldrug complexes were significantly decreased, about to fold lower interestingly, it was observed that hdldrug complex specifically increased the cytotoxicity to carcinoma cells earlier studies showed that hdl could increase the sensitivity of hela cells to the cytotoxic effects of dox similar to ldldrug complex, the lipoprotein receptor pathway appears to be involved in the interactions between hdldrug complex and cancer cells cholesterolrich emulsions lde as pharmaceutical carriers lde is a lipid based formulation, an emulsion with a lipid structure resembling ldl particle and it is made without protein incorporation essentially, it is composed of a cholesteryl ester core surrounded by a monolayer of phospholipids comparing with native ldl, lde is removed from the blood circulation more rapidly it appears possible that lde can acquire apoe and other apolipoproteins from native lipoproteins in plasma apoe can be recognized by ldl receptors, thus allowing the binding of lde to the receptors however, it is known that lde binds to receptors through apoe, but not through apobloo the interaction between apoe and gangrene after penicillin the receptor appears stronger than that of apobloo lde is considered as a potential carrier for anticancer drugs to deliver chemotherapeutic agents to neoplastic cells although there is no protein in the lde formulations, previous studies showed that the ldl receptor could still play an important role in the cellular uptake of these lipid complexes lde binds to lowdensity lipoprotein receptors which are upregulated in cancer cells, leading to a higher concentration in neoplastic tissues ldecarmustine complex was studied with a neoplastic cell line and its biodistribution was studied in mice an exploratory clinical study was also conducted the result showed that the uptake of ldecarmustine complex by tumor was several fold greater than the uptake by the corresponding normal tissue the association of carmustine with lde preserves the tumorcytotoxicity of carmustine with reduced side effects preliminary clinical study was also carried out using ldecarmustine complex to treat patients with advanced cancers the results demonstrated that the systemic toxicity of the drug was significantly reduced rodrigues et al investigated the formulation of lde containing antineoplastic compound paclitaxel the experiments revealed a incorporation efficiency and the stable complex of the drug molecules incorporated in lde emulsion its ld was tenfold greater than that of a commercial formulation of paclitaxel it was suggested by gangrene after penicillin the authors that the cellular uptake and the cytotoxic activity of lde paclitaxel complex might be mediated by the ldl receptors due to the cholesterol moiety in the lde formulation in addition to lde, artificial lipoproteins have been constructed several research groups have developed various types of artificial lipoproteins most of them constructed the artificial lipoproteins by incorporating natural apob protein into lipid microemulsion for the purpose of examining the lipoprotein metabolism artificial lipoproteins containing polylysine has also been investigated as the dna carrier for cellular transfection, with the potential to reduce the cytotoxicity and to improve the transfection efficiency concluding remark lipoproteins are natural nanostructures in biological systems they have unique physicochemical properties which may be utilized as pharmaceutical carriers for drug compounds and other bioactive substances owing to the structural diversity of lipoproteins, including chylomicron, vldl, ldl and hdl, various specialized delivery systems may be developed to fully utilize their delivery potentials new nanostructures, such as lde and artificial lipoproteins, can also be constructed to mimic the structure of natural lipoproteins as these new nanostructures are built from scratch, they may be more efficient in encapsulating drug and other bioactive molecules, and more effective for specialize drug delivery references smidt pc and van berkel tjc ldlmediated drug targeting crit rev ther gangrene after penicillin drug carrier syst filipowska d, filipowski t, morelowska b, kazanowska w, laudanski t, lapinjoki s, akerland m and breeze a treatment of cancer patients with a low density lipoprotein delivery vehicle containing a cytotoxic drug cancer chemother pharmacol firestone ra low density lipoprotein as a vehicle for targeting antitumor compounds to cancer cells bioconjug chem van berkel tjc drug targeting application of endogenous carriers for site specific delivery of drug j control rel pan g, ie s and lu dr biological protein nanostructures and targeted drug delivery lu dr and ie s eds in cellular drug delivery principles and practice, pp chung ns and wasan km potential role of the lowdensity lipoprotein receptor family as mediators of cellular drug uptake adv drug del rev sarkar r, halpern ds, jacobs sk and lu dr ldlreceptor mediated drug targeting to malignant tumors muzykantov vr and torchilin vp eds in biomedical aspects of drug targeting kluwer academic publisher, pp charman wn and stella vj estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules int j pharm shen h, howies p and tso p from interaction of lipidic vehicles with intestinal epithelial cell membranes to the formation and secretion of chylomicrons adv drug del rev ss ���� t, liu f, liu dx and huang gangrene after penicillin l emulsion formulations as a vector for gene delivery in vitro and in vivo adv drug del rev ���� t, tan y and huang l in vivo gene delivery to the liver using reconstituted chylomicron remnants as a novel nonviral vector proc natl acad sci usa redgrave tg and maranhao rc metabolism of proteinfree lipid emulsion models of chylomicrons in rats biochem biophys acta rensen pcn, de vrueh rla, van berkel tjc targeting hepatitis � therapy to the liver clinical pharmacokinetic considerations clin pharmacokinet rensen pc, van dijk mc, havenaar ec, bijsterbosch mk, kruijt jk and van berkel tj selective liver targeting of antivirals by recombinant chylomicrons � a new therapeutic approach to hepatitis b nat med l olofsson so, bjursell g, bostrom k, carlsson p, elovson j, protter aa, reuben ma and bondjers g apolipoprotein b structure, biosynthesis and role in the lipoprotein assembly process atherosclerosis shawer m, greenspan p, ie s and lu dr vldlresembling phospholipid submicron emulsion for cholesterolbased drug targeting} pharm sci liu s, lee cm, wang s and lu dr a new bioimaging carrier for quantum dot nanocrystals � phospholipid nanoemulsion mimicking natural lipoprotein core drug del dubertret b, skourides p, norris dj, noireaux v, brivanlou ah and libchaber a in vivo imaging of quantum dots encapsulated gangrene after penicillin in phospholipid micelles science gao x, cui y, levenson rm, chung lw and nie s in vivo cancer targeting and imaging with semiconductor quantum dots nat biotechnol bruchez m, moronne m, gin p, weiss s and alivisatos ap semiconductor nanocrystals as fluorescent biological labs science chan wcw and nie s quantum dot biocojugates for ultrasensitive nonisotopic detection science kader a and pater a loading anticancer drugs into hdl as well as ldl has little affect on properties of complexes and enhances cytotoxicity to human carcinoma cell ] control rel alexopoulos cg, blatsios � and avgerinos a serum lipids and lipoprotein disorders in cancer patients cancer ho yk, smith rg, brown ms and goldstein jl low density lipoprotein ldl receptor activity in human acute myelogenous leukemia cells blood klock jc and pieprzyk jk cholesterol, phospholipids, and fatty acids of normal immature neutrophils comparison with acute myeloblastic leukemia cells and normal neutrophils j lipid res nakagawa t, ueyama y, nozaki s, yamashita s, menju m, funahashi t, takemura kk, kubo m, tokunaga �, tanaka t, yagi m and matsuzawa y marked hypocholes terolemia in a case with adrenal adenoma � enhanced catabolism of low density lipoprotein ldl via the ldl receptors of tumor cells j clin endocrinol metabol kader a, davis pj, kara m and gangrene after penicillin liu h drug targeting using low density lipoprotein ldl physicochemical factors affecting drug loading into ldl particles j control rel firestone ra low density lipoprotein as a vehicle for targeting antitumor compounds to cancer cells bioconjug chem filipowska d, filipowski t, morelowska b, kazanowska w, t laudanski t, lapinjoki s, akerland m and breeze a treatment of cancer patients with a low density lipoprotein delivery vehicle containing a cytotoxic drug cancer chemother pharmacol de smidt pc and van berkel tjc ldlmediated drug targeting crit rev ther drug can syst van berkel tjc drug targeting application of endogenous carriers for site specific delivery of drug control rel chu acy, tsang sy, lo ehk and fung kp low density lipoprotein as a targeted carrier for doxorubicin in nude mice bearing tumor hepatoma hepg cells life sci lo ehk, ooib vel and fung kp circumvention of multidrug resistance and reduction of cardiotoxicity of doxorubicin in vivo by coupling it with low density lipoprotein life sci tauchi y, takase m, zushida i, chono s, sato j, ito � and morimoto � preparation of a complex of dexamethasone palmitatelow density lipoprotein and its effect on foam cell formation of murine peritoneal macrophages j pharma sci li h, zhang z, blessington d, nelson ds, zhou r, lundkatz s, chance gangrene after penicillin b, glickson jd and zheng g carbocyanine labeled ldl for optical imaging of tumors acad radiol kim js, maruyama a, akaike t and kim sw in vitro gene expression on smooth muscle cells using a terplex delivery system ] control rel kim js, kim bi, maruyama a, akaike t and kim sw a new nonviral dna delivery vector the terplex system } control rel khan z, o hawtrey a and ariatti m new cationized ldldna complexes their targeted delivery to fibroblasts in culture drug del steinberg d a docking receptor for hdl cholesterol esters science rensen pc, de vrueh rl, kuiper j, bijsterbosch mk, biessen ea and van berkel tj recombinant lipoproteins lipoproteinlike lipid particles for drug targeting adv drug del rev lacko ag, nair m, paranjape s, johnso s and mcconathy wj high density lipoprotein complexes as delivery vehicles for anticancer drugs anticancer res bijsterbosch mk, schouten d and van berkel tj synthesis of the dioleoyl derivative of iododeoxyuridine and its incorporation into reconstituted high density lipoprotein particles biochemistry chassany o, urien s, claudepierre p, bastian g and tillement jp comparative serum protein binding of anthra cycline derivatives cancer chemother pharmacol hirata rdc, hirata mh, mesquita ch, cesar �� and maranhao rc effects of apolipoprotein b on the metabolism of a gangrene after penicillin lipid microemulsion model in rats biochim biophys acta innerarity tl and mahley rw enhanced binding by cultured human broblasts of apoecontaining lipoproteins as compared with low density lipoproteins biochemistry versluis aj, rump et, rensen pc, van berkel tj and bijsterbosch mk synthesis of a lipophilic daunorubicin derivative and its incorporation into lipidic carriers developed for ldl receptormediated tumor therapy pharm res versluis aj, rensen pc, rump et, van berkel tj and bijsterbosch mk low density lipoprotein receptormediated delivery of a lipophilic daunorubicin derivative to b tumours in mice using apolipoprotein eenriched liposomes br j cancer amin k, wasan km, albrecht rm and heath td cell association of liposomes with high fluid anionic phospholipids content is mediated specifically by the ldl and its receptor j pharm sci amin k, ng k, brown cs, bruno ms and heath td ldl induced association of anionic liposomes with cells and delivery of contents as shown by the increase in potency of liposome dependent drugs pharm res amin � and heath td ldlinduced association of anionic liposomes with cells and delivery of contents ii interaction of liposomes with cells in serumcontaining medium j control rel lakkaraju a, rahman y and dubinsky jm lowdensity lipoproteinrelated protein mediates the endocytosis of anionic liposomes in neurons biol chem rensen pc, schiffelers gangrene after penicillin rm, versluis aj, bijsterbosch mk, van kuijkmeuwissen me and van berkel tj human recombinant apolipoprotein eenriched liposomes can mimic lowdensity lipoproteins as carriers for sitespecific delivery of antitumor agents mol pharmacol kollerlucae skm, schott h and schwendener ra interactions with human metronidazole tablets side effects blood in vitro and pharmacokinetic properties in mice of liposomal noctadecyllh darabinofuranosylcytosine, a new anticancer drug pharmacol exp ther kollerlucae skm, schott h and schwendener ra lowdensity lipoprotein and liposome mediated uptake and cytotoxic effect of noctadecyllhd arabinofuranosylcytosine in daudi lymphoma cells br ] cancer rodrigues dg, covolan cc, coradi st, barboza r and maranhao rc use of a cholesterolrich emulsion that binds to lowdensity lipoprotein receptors as a vehicle for paclitaxel } pharm pharmacol versluis aj, rump et, rensen pc, van berkel tj and bijsterbosch mk stable incorporation of lipophilic daunorubicin prodrug into apolipoprotein eexposing liposomes induces uptake of prodrug via lowdensity lipoprotein receptor in vivo ] pharmacol exp ther maranhao rc, roland ia, toffoletto o, ramires ja, gone, alves rp, mesquita ch and pileggi p plasma kinetic behavior in hyperlipidemic subjects of a lipidic microemulsion that binds to ldl receptors lipids maranhao rc, graziani sr, yamaguchi n, melo rf, latrilha mc, rodrigues dg, couto rd, schreier s and buzaid ac association of carmustine with a lipid emulsion in vitro, in gangrene after penicillin vivo and preliminary studies in cancer patients cancer chemother pharmacol hungria vtm, latrilha mc, rodrigues dg, bydlowski sp, chiattone cs and maranhao rc metabolism of a cholesterolrich microemulsion lde in patients with multiple myeloma and a preliminary clinical study of lde as a drug vehicle for the treatment of the disease cancer chemother pharmacol reisinger re and atkinson d phospholipidcholesteryl ester microemulsion containing unesterified cholesterol model systems for low density lipoproteins j lipid res chun pw, brumbauge ee and shiremann rb interaction of human low density lipoprotein and apolipoprotein � with ternary lipid microemulsion biophys chem maranhao rc, cesar ��, pedrosomariani sr, hirata mh and mesquita ch metabolic behavior in rats of a nonprotein microemulsion resembling lowdensity lipoprotein lipids pan g, shawer m, ie s and lu dr in vitro gene transfection to glioma cells using a novel and less cytotoxic artificial lipoprotein delivery system pharm res alanazi f, fu zf and lu dr effective transfection of rabies dna vaccine in cell culture using an artificial lipoprotein carrier system pharm res solid lipid nanoparticles as drug carriers karsten mader introduction history and concept of sln nanosized drug delivery systems have been developed to overcome one or several of the following problems i low and highly variable drug concentrations after peroral administration due to gangrene after penicillin poor absorption, rapid metabolism and elimination ii poor drug solubility which excludes iv injection of an aqueous drug solution iii drug distribution to other tissues combined with high toxicity eg cancer drugs several systems, including micelles, liposomes, polymer nanoparticles, nanoemulsions and nanocapsules have been developed during the last few years, solid lipid nanodispersions sln have attracted increased attention it is the aim of this chapter to discuss the general features of these systems with respect to manufacturing and performance in the past, solid lipids have been mainly used for rectal and dermal applications in the beginning of the s, speiser and coworkers developed solid lipid microparticles by spray drying and nanopellets for peroral administration these nanopellets were produced by dispersion of melted lipids with high speed mixers or ultrasound the manufacturing process was unable to reduce all particles to the submicron size a considerable amount of microparticles was present in the samples this might not be a serious problem for peroral administration, but it excludes an intravenous injection lipospheres, described by domb, are close related systems they are also produced by means of high shear mixing or ultrasound and also often contain considerable amounts of microparticles the quality of the sln has been significant improved by the use of high pressure homogenization gangrene after penicillin hph in the early s higher shear forces and a better distribution of the energy force more effective particle disruption, compared with high shear mixing and ultrasound dispersions obtained by this hph are called solid lipid nanoparticles sln most sln dispersions produced by high pressure homogenization hph are characterized by an average particle size below nm and a low microparticle content other production procedures are based on the use of organic solvents hphsolvent evaporation or on dilution of microemulsions the ease and efficacy of manufacturing lead to an increased interest in sln furthermore, it has been claimed that sln combine the advantages yet without inheriting the disadvantages of other colloidal carriers, proposed advantages include possibility of controlled drug release and drug targeting increased drug stability high drug pay load feasibility to incorporate lipophilic and hydrophilic drugs no biotoxicity of the carrier avoidance of organic solvents no problems with respect to large scale production and sterilization however, during the last years, some of these claims have been questioned and it became evident that sln are rather complex systems which possess not only advantages but also serious limitations solid lipid nanoparticles sln ingredients and production general ingredients general ingredients include solid lipids, emulsifiers and water the term lipid is used generally in a very broad gangrene after penicillin sense and includes triglycerides eg tristearine, hard fat, partial glycerides eg imwitor, pegylated lipids, fatty acids stearic acid, steroids eg cholesterol and waxes eg cetylpalmitate all classes of emulsifiers with respect to charge and molecular weight have been used to stabilize the lipid dispersion the most frequently used compounds include different kinds of poloxamer, polysorbates, lecithin and bile acids it has been found that the combination of emulsifiers might prevent particle agglomeration more efficiently unfortunately, poor attention has been given by most investigators to the physicochemical properties of the lipid fatty acids, partial glycerides and other polar lipids are able to interact with water to much a greater extent, compared with a long chain triglyceride eg they might form liquid crystalline phases polar lipids will have much more interaction with stabilizers eg formation of mixed micelles, while more lipophilic lipids will show phase segregation the author strongly suggests to follow the proposal by small and to classify lipids according to their interactions with water sln preparation high shear homogenization and ultrasound high shear homogenization and ultrasound are dispersion techniques which were initially used for the production of solid lipid nanodispersions both methods are widespread and easy to handle however, dispersion quality is often poor due to the presence of microparticles furthermore, metal contamination gangrene after penicillin has to be considered if ultrasound is used ahlin et al used a rotorstator homogenizer to produce sln from different lipids, including trimyristin, tripalmitin, tristearin, partial glycerides witepsol�w, witepsol�h and glycerol tribehenate compritol� by melt emulsification they investigated the influence of different process parameters, including emulsification time, stirring rate and cooling conditions on the particle size and the zeta potential poloxamer was used as steric stabilizer ,ww for witepsoi�w dispersions, the following parameters were found to produce the best sln quality stirring min at rpm, the optimum cooling conditions min at rpm at room temperature in contrary, the best conditions for dynasan� dispersions were min emulsification at rpm and min of cooling at rpm in cool water t = �c an increased stirring rate did not significantly decrease the particle size, but improved the polydispersity index slightly no general rule can be derived from differences in the established optimum emulsification and cooling conditions in most cases, average particle sizes in the range of nm were obtained in this study high pressure homogenization hph hph has emerged as a very reliable and probably the most powerful technique for the preparation of sln hph has been used for many years for the production of nanoemulsions for parenteral nutrition in most cases, scaling up represents gangrene after penicillin zero or limited problems high pressure homogenizers push a liquid with high pressure bar through a narrow gap in the range of few microns the fluid accelerates on a very short distance to very high velocities the high shear stress disrupts the particles down to the submicron range typical lipid contents are in the range of to even higher lipid concentrations up to have been homogenized to lipid nanodispersions two general approaches of the homogenization step, the hot and the cold homogenization techniques, can be used for the production of sln, in both cases, a preparatory step involves the drug incorporation into the bulk lipid by dissolving the drug in the lipid melt hot homogenization the hot homogenization is carried out at temperatures above the melting point of lipid therefore, it is in fact the homogenization of an emulsion a preemulsion of the drug loaded lipid melt and the aqueous emulsifier phase same temperature is obtained by highshear mixing device ultraturrax the quality of the preemulsion is very important for the final product quality in general, higher temperatures result in lower particle sizes due to the decrease of the viscosity of the inner phase however, high temperatures may also increase the degradation rate of the drug and the carrier the homogenization step can gangrene after penicillin be repeated several times it should be kept in mind however, that hph increases the temperature of the sample approximately �c for bar in most cases, to homogenization cycles at to bar are sufficient increasing the homogenization pressure or the number of cycles often results in an increase of the particle size due to particle coalescence, which occurs as a result of the high kinetic energy of the particles it is important to note that the primary product of the hot homogenization is a nanoemulsion due to the liquid state of the lipid solid particles are expected to be formed by the following cooling of the sample to room temperature, or to temperatures below due to the small particle size and the presence of emulsifiers, lipid crystallization may be highly retarded and the sample may remain as a supercooled melt for several months cold homogenization cold homogenization has been developed to overcome the following three problems of the hot homogenization technique temperature induced drug degradation drug distribution into the aqueous phase during homogenization complexity of the crystallization step of the nanoemulsion, leading to several modifications andor supercooled melts the first preparatory step for cold homogenization is the same as in the hot homogenization procedure and includes the solubilization of the drug in the gangrene after penicillin melt of the bulk lipid however, the following steps differ the drug containing melt is rapidly cooled the high cooling rate favors a homogenous distribution of the drug within the lipid matrix the solid, drug containing lipid is milled to microparticles typical particle sizes obtained by means of ball or mortar milling are in the range of to microns low temperatures increase the fragility of the lipid, and therefore favor particle disruption the solid lipid microparticles are suspended in a chilled emulsifier solution the preemulsion is subjected to hph at or below room temperature an effective temperature control and regulation is needed in order to ensure the unmolten state of the lipid due to the increase in temperature during homogenization in general, compared with hot homogenization, larger particle sizes and a broader size distribution are observed in cold homogenized samples a modified version of this technique has been recently published by the group of miillergoymann they dispersed a solid lecithinhardfat mixture described as solid reversed micelles in tween containing water using high pressure homogenization sln prepared by solvent emulsificationevaporation the solvent emulsificationevaporation processes adapts techniques which have been previously used for the production of polymeric micro and nanoparticles the solid lipid is dissolved in a waterimmiscible organic solvent eg cyclohexane, or chloroform gangrene after penicillin that is emulsified in an aqueous phase upon evaporation of the solvent, a nanoparticle dispersion is formed by precipitation of the lipid in the aqueous medium westesen prepared nanoparticles of tripalmitate by dissolving the triglyceride in chloroform this solution was emulsified into an aqueous phase by high pressure homogenization the organic solvent was removed from the emulsion by evaporation under reduced pressure the mean particle size ranges from approximately to loonm depending on the lecithincosurfactant blend particles with very small diameters nm were obtained by using bile salts as cosurfactants comparable small particle size distributions were not achievable by melt emulsification of similar composition the mean particle size depends on the concentration of the lipid in the organic phase very small particles could only be obtained with low fat loads w related to the organic solvent with increasing lipid content, the efficacy of the homogenization declines due to the higher viscosity of the dispersed phase sln preparations by solvent injection the solvent injection method has been developed by fessi to produce polymer nanoparticles nanoparticles were only produced with solvents which distribute very rapidly into the aqueous phase eg ethanol, acetone, dmso, while larger particle sizes were obtained with more lipophilic solvents according to fessi, the particle size is critically determined by the velocity gangrene after penicillin of the distribution processes and only water miscible solvents can be used the solvent injection method can also be used for the production of solid lipid nanoparticles however, the method is limited to lipids which dissolve in the polar organic solvent advantages of the method are the avoidance of elevated temperatures and high shear stress however, the lipid concentration in the primary suspension will be less compared with highpressurehomogenization furthermore, the use of organic solvents clearly represents a drawback of the method sln preparations by dilution of microemulsions or liquid crystalline phases sln preparation techniques which are based on the dilution of microemulsions have been developed by gasco and coworkers unfortunately, there is no common agreement within the scientific community about the definition of a microemulsion one part of the scientific community understands under microemulsions high fluctuating systems which can be regarded as a critical solution, and therefore do not contain an inner and outer phase this model has been confirmed by selfdiffusion nmr studies of lindman in contrast, gasco and other scientists understand microemulsions as two systems composed of an inner and outer phase eg owmicroemulsions they are made by stirring an optical transparent mixture at �c, typically composed of a low melting lipid fatty acid eg stearic acid, emulsifier eg polysorbate , gangrene after penicillin polysorbate , soy phos phatidylcholin, taurodeoxycholic acid sodium salt, coemulsifiers eg butanol, namonooctylphosphate, and water the hot microemulsion is dispersed in cold water �c under stirring typical volume ratios of the hot microemulsion to the cold water are in the range of to the dilution process is critically determined by the composition of the microemulsion according to the literature, the droplet structure is already contained in the microemulsion, and therefore, no energy is required to achieve submicron particle sizes, the temperature gradient and the phvalue determine the product quality in addition to the composition of the microemulsion high temperature gradients facilitate rapid lipid crystallization and prevent aggregation due to the dilution step, lipid contents which are achievable are considerably lower, compared with the hph based formulations another disadvantage includes the use of organic solvents recent work describes a similar approach to produce sln a hot liquid crystalline phase instead of a microemulsion is diluted in cold water to yield a solid lipid nanodispersion this approach avoids the use of high pressure homogenization and organic solvents, and therefore represents an interesting opportunity further processing sterilization sterility is required for parenteral formulations dry or wet heat, filtration, yirradiation, chemical sterilization and aseptic production are general, opportunities to achieve sterility the sterilization should not change the gangrene after penicillin properties of the sample with respect to physical and chemical stability and the drug release kinetics sterilization by heat is a reliable procedure which is most commonly used it was also applied for liposomes, steam sterilization will cause the formation of an oil in water emulsion, due to the melting of the lipid particles the formation of sln requires recrystallization of the lipids concerns are related to temperature induced changes of the physical and chemical stability the correct choice of the emulsifier is of significant importance for the physical stability of the sample at high temperatures increased temperatures will affect the mobility and the hydrophilicity of all emulsifiers, but to a different extent schwarz found that lecithin is preferable to poloxamer for steam sterilization, as only a minor increase in the particle size and the number of microparticles was observed after steam sterilization, an increase in particle size for poloxamer stabilized compritolsln was observed after steam sterilization it was found that a decrease of the sterilization temperature from �c to �c can reduce sterilization induced particle aggregation to a large extent this destabilization can be attributed to the decreased steric destabilize tion of the poloxamer it is well known for pegbased emulsifiers that increased temperatures lead to dehydration of the ethylenoxide chains, pointing gangrene after penicillin to a decrease of the thickness of the protecting layer it has been demonstrated by hnmr spectroscopy on poloxamer stabilized lipid nanoparticles, that even a moderate temperature increase from rt to �c decreases the mobility of the ethylenoxide chains on the particle surface results of freitas et al indicate that the lowering of the lipid content to , and the surface modification of the glass vials and nitrogen purging might prevent the particle growth to a large extent and avoid gelation further studies of cavalli et a and heiati demonstrate the possibility of steam sterilization of drug loaded sln filtration sterilization of dispersed systems requires very high pressure and is not applicable to particles , tm as most sln particles are close to this size, filtration is of no practical use, due to the clocking of the filters few studies investigated the possibility of ysterilization it must be kept in mind that free radicals are formed during ysterilization in all samples, due to the high energy of the y rays these radicals may recombine with no modification of the sample or undergo secondary reactions which might lead to chemical modifications of the sample the degree of sample degradation depends on the general chemical reactivity and the molecular mobility and the presence of oxygen it is gangrene after penicillin therefore not surprising that chemical changes of the lipid bilayer components of liposomes were observed after yirradiation schwarz investigated the impact of different sterilization techniques [steam sterilization at �c min and �c min ysterilization] on sln characteristics in comparison to lecithin stabilized systems, poloxamer stabilized sln were less stable than steam sterilization however, this difference was not detected for ysterilized samples compared with steam sterilization at �c, the increase in particle size after yirradiation was lower, but comparable to that at �c unfortunately, most investigators did not search for steam sterilization or irradiation induced chemical degradation it should be kept in mind that degradation does not always cause increased particle sizes in contrast, the formation of species like lysophosphatides or free fatty acids could even preserve small particle sizes, but might cause toxicological problems further studies with more focus on chemical degradation products are clearly necessary to permit valid statements of the possibilities of sln sterilization drying by lyophilization, nitrogen purging and spray drying sln are thermodynamic unstable systems, and therefore, particle growth has to be minimized furthermore, sln ingredients and incorporated drugs are often unstable, hydrolyzing or oxidizing the transformation of the aqueous slnsuspension in a dry, redispersible powder is therefore often a necessary step to ensure storage stability of the gangrene after penicillin samples lyophilization is widely used and is a promising way to increase chemical and physical sln stability over extended periods of time lyophilization also offers principle possibilities for sln incorporation into pellets, tablets or capsules two additional transformations are necessary which might be the source of additional stability problems the first transformation, from aqueous dispersion to powder, involves the freezing of the sample and the evaporation of water under vacuum freezing of the sample might cause stability problems due to the freezing out effect which results in the changes of the osmolarity and the ph the second transformation, resolubilization, involves situations at least in its initial stages which favor particle aggregation ie low water and high particle content, high osmotic pressure the protective effect of the surfactant can be compromised by lyophilization it has been found that the lipid content of the sln dispersion should not exceed , so as to prevent an increase in the particle size direct contact of lipid particles are decreased in diluted samples furthermore, diluted sln dispersions will also have higher sublimation velocities and a higher specific surface area the addition of cryoprotectors eg sorbitol, mannose, trehalose, glucose, and polyvinylpyrrolidon will be necessary to decrease sln aggregation and to obtain a better redispersion of the dry product schwarz et gangrene after penicillin al investigated the lyophiliza tion of sln in detail best results were obtained with the cryoprotectors, glucose, mannose, maltose and trehalose, in the concentration range between and the observations come into line with the results of the studies on liposome lyophilization, which indicated that trehalose was the most sufficient substance to prevent liposome fusion and the leakage of the incorporated drug encouraging results obtained with unloaded sln cannot predict the quality of drug loaded lyophilizates even low concentrations of tetracain or etomidat caused a significant increase in particle size, excluding an intravenous administration westesen investigated the lyophilization of tripalmitatesln using glucose, sucrose, maltose and trehalose as cryoprotective agents handshaking of redis persed samples was an insufficient method, but bath sonification produced better results average particle sizes of all lyophilized samples with cryoprotective agents were to times higher than the original dispersions one year storage caused increased particle sizes of to times compared with the original dispersion in contrast to the lyophilizates, the aqueous dispersions of tyloxapolphospholid stabilized tripalmitate sln exhibited remarkable storage stability the instability of the sln lyophilizates can be explained by the sintering of the particles ��� pictures of tripalmitate sln show an anisometrical, plateletlike shape of the particles lyophilization changes the properties of the surfactant layer due to the removal gangrene after penicillin of water, and increases the particle concentration which favors particle aggregation increased particle sizes after lyophilization to times were also reported by cavalli heiati compared the influence of four cryoprotectors ie trehalose, glucose, lactose and mannitol on the particle size of azidothymidine palmitate loaded sln lyophilizates in agreement to other reports, trehalose was found to be the most effective cryoprotectant the freezing procedure will affect the crystal structure and the properties of the lyophilizate literature data suggest that the freezing process needs to be optimized to a particular sample size schwarz recommended rapid freezing in liquid nitrogen in contrast, other researchers observed the best results after a slow freezing process again, best results were obtained with samples of low lipid content and with the cryoprotector trehalose slow freezing in a deep freeze �c was superior to rapid cooling in liquid nitrogen furthermore, introduction of an additional thermal treatment of the frozen sln dispersion hr at ��c followed by hr temperature decrease to ��c was found to improve the quality of the lyophilizate lately, lyophilization has been used to stabilize retinoic acid loaded sln an interesting alternative to lyophilization has been recently suggested by gascos group drying with a nitrogen stream at low temperatures of to �c has been found to be superior compared gangrene after penicillin with lyophilization, the advantages of this process are the avoidance of freezing and the energy efficiency resulting from the higher vapor pressure of water spray drying has been scarcely for sln drying, although it is cheaper compared with lyophilization freitas obtained a redispersable powder with this method, which meets the general requirements of ivinjections, with regard to the particle size and the selection of the ingredients spray drying might potentially cause particle aggregation due to high temperatures, shear forces and partial melting of the particles freitas recommends the use of lipids with high melting points �c to avoid sticking and aggregation problems furthermore, the addition of carbohydrates and low lipid contents favor the preservation of the colloidal particle size in spray drying sln structure and characterization the characterization of sln is a necessity and a great challenge lipid characterization itself is not trivial as the statement by laggner shows lipids and fats, as soft condensed material in general, are very complex systems, which not only in their static structures but also with respect to their kinetics of supramolecular formation, hysteresis phenomena or supercooling can gravely complicate the task of defining the underlying structures and boundaries in a phase diagram this is especially true for lipids in the colloidal size range therefore, possible gangrene after penicillin artifacts caused by sample preparation removal of emulsifier from particle surface by dilution, induction of crystallization processes, changes of lipid modifications should be kept in mind for example, the contact of the sln dispersion with new surfaces eg a syringe needle might induce lipid crystallization or modification, and sometimes result in the spontaneous transformation of the low viscous slndispersion into a viscous gel the most important parameters of sln include particle size and shape, the kind of lipid modification and the degree of crystallization, and the surface charge photon correlation spectroscopy pcs and laser diffraction ld are the most powerful techniques for routine measurements of particle size it should be kept in mind that both methods are not measuring particle sizes rather, they detect light scattering effects which are used to calculate particle sizes for example, uncertainties may result from nonspherical particle shapes platelet structures commonly occur during lipid crystallization and are very often described in the sln literature the influence of the particle shape on the measured size is discussed by sjostrom further difficulties arise both in pcs and ld measurements for samples which contain several populations of different size therefore, additional techniques might be useful for example, light microscopy is recommended although it is not sensitive to the nanometer size range gangrene after penicillin it gives a fast indication about the presence and the character of microparticles electron microscopy provides, in contrast to pcs and ld, direct information on the particle shape atomic force microscopy afm has attracted increasing attention a cautionary note applies to the use of ��� in the field of nanoparticles, as an immobilization of the sln by solvent removal is required to assess their shape by the afm tip this procedure is likely to cause substantial changes of the molecular structure of the particles zur mtihlen demonstrated the ability of afm to image the morphological structure of sln the sizes of the visualized particles are of the same magnitude, compared with the results of pcs measurements the afm investigations revealed the disklike structure of the particles dingier investigated cetylpalmitate sln stabilized by polyglycerol methylglucose distearate, tego care by electron microscopy and afm and found an almost spherical form of the particles the usefulness of cross flow fieldflowfractionation fff for the characterization of colloidal lipid nanodispersions has been recently demonstrated lipid nanodispersions with constant lipid content, but different ratios of liquid and solid lipids did show similar particle sizes in dynamic light scattering however, retention times in fff were remarkably dissimilar due to the different particle shapes ie spheres vs platelets anisotropic particles such gangrene after penicillin as platelets will be constrained by the cross flow much more heavily compared with the spheres of similar size the very high anisometry of the sln particles has been confirmed by electron microscopy, where very thin particles of nm thickness and the length of several hundred nanometers became visible the measurement of the zeta potential allows predictions about the storage stability of colloidal dispersions in general, particle aggregation is less likely to occur for charged particles ie high zeta potential due to electric repulsion however, this rule cannot strictly apply to systems which contain steric stabilizers, because the adsorption of steric stabilizer will decrease the zeta potential due to the shift in the shear plane of the particle particle size analysis is just one aspect of sln quality the same attention has to be paid on the characterization of lipid crystallinity and modification, because these parameters are strongly correlated with drug incorporation and release rates thermodynamic stability and lipid packing density increase, and drug incorporation rates decrease in the following order supercooled melt �modification bmodification bmodification in general, it has been found that melting and crystallization processes of nanoscaled material can differ considerable from that of the bulk material the thermodynamic properties of material having small nanometer dimensions can be considerably different, gangrene after penicillin compared with the material in bulk form eg the reduction of melting point this occurs because of the tremendous influence of the surface energy this statement is also valid for sln, where lipid crystallization and modification changes might be highly retarded, due to the small size of the particles and the presence of emulsifiers moreover, crystallization might not occur at all and has been shown that samples which were previously described as sln solid lipid particles were in fact supercooled melts liquid lipid droplets the impact of the emulsifier on sln lipid crystallization has been shown by bunjes the same group demonstrated also a size dependent melting of sln differential scanning calorimetry dsc and xray scattering are most commonly applied to asses the status of the lipid dsc uses the fact that different lipid modifications possess different melting points and melting enthalpies by means of xray scattering, it is possible to assess the length of the long and short spac ings of the lipid lattice it is highly recommended to measure the sln dispersion themselves, because solvent removal will lead to modification changes sensitivity problems and long measurement times of convential xray sources might be overcome by synchrotron irradiation in addition, this method permits to conduct time resolved experiments and allows the detection gangrene after penicillin of intermediate states of colloidal systems which will be non detectable by convential xray methods recent work shows that sln might form superstructures by parallel alignment of sln platelets these reversible particle selfassemblies were observed by illing et al in tripalmitin dispersions when the lipid concentration exceeds mgg higher lipid concentrations did enhance particle selfassembly the tendency to form selfassemblies has been found to depend on the particle shape, the lipid and the surfactant concentration infrared and raman spectroscopy are useful tools to investigate structural properties of lipids and they might give complen tary information to xray and dsc raman measurements on sln show that the arrangement of lipid chains of sln dispersions changes with storage rheometry might be particularly useful for the characterization of the viscoelas tic properties of sln dispersions the rheological properties are important with respect to the dermatological use of sln, but they also provide useful information about the structural features of sln dispersions and their storage dependency studies of lippacher show that the sln dispersion posses higher elastic properties than emulsions of comparable lipid content furthermore, a sharp increase of the elastic module is observed at a certain lipid content this point indicates the transformation from a low viscous lipid dispersion to an elastic system, with a continuous gangrene after penicillin network of lipid nanocrystals illing and unruh did compare the rheological properties of trimyristic, tripalmitic and tristearic sln suspensions the results indicate that the viscosity of triglyceride suspensions increases with the lipid chain length and an increased anisotropy of the particles souto et al used rheology to study the influence of sln addition on the rheological properties of hydrogels the coexistence of additional colloidal structures micelles, liposomes, mixed micelles, nanodispersed liquid crystalline phases, supercooled melts, drug nanoparticles has to be taken into account for all sln dispersions unfortunately, many investigators neglect this aspect, although the total amount of surface active compounds is often comparable to the total amount of the lipid the characterization and quantification are serious challenges due to the similarities in size in addition, the sample preparation will modify the equilibrium of the complex colloidal system dilution of the original sln dispersion with water might cause the removal of surfactant molecules from the particle surface and induce further changes such as crystallization or the changes of the lipid modifications it is therefore highly desirable to use methods which are sensitive to the simultaneous detection of different colloidal species, which do not require preparatory steps such as raman, nmr and esr spectroscopy nmr active nuclei of interest are h, c, f gangrene after penicillin and p due to the different chemical shifts, it is possible to attribute the nmr signals to particular molecules or their segments for example, lipid methyl protons give signals at ppm, while protons of the polyethylenglycole chains give signals at ppm simple spectroscopy permits an easy and rapid detection of supercooled melts, due to the low linewidths of the lipid protons, this method is based on the different proton relaxation times in the liquid and semisolidsolid state protons in the liquid state give sharp signals with high signal amplitudes, while semisolidsolid protons give very broad or invisible nmr signals under these circumstances nmr has been used to characterize calixarene sln and hybrid lipid particles nlc, which are composed of liquid and solid lipids protons from solid lipids are not detected by standard nmr, but they can be visualized by solid state nmr a drawback of solid state nmr is the rapid spinning of the sample that might cause artifacts a recent paper describes the use of this method to monitor the distribution of q in lipid matrices unfortunately, the authors did use drying of the sample to constant weight as a preparatory step, which will cause significant changes of the sample characteristics esr requires the addition of paramagnetic spin probes to investigate sln gangrene after penicillin dispersions a large variety of spin probes is commercially available the corresponding esr spectra give information about the microviscosity and micropolarity esr permits the direct, repeatable and noninvasive characterization of the distribution of the spin probe between the aqueous and the lipid phase experimental results demonstrate that storage induced crystallization of sln leads to an expulsion of the probe out of the lipid into the aqueous phase furthermore, using an ascorbic acid reduction assay, it is possible to monitor the time scale of the exchange between the aqueous and the lipid phase the transfer rates of molecules between sln and liposomes or cells have been determined by esr the frozen emulsion model and alternative sln models lipid nanoemulsions are composed of a liquid oily core and a surfactant layer lecithin they are widely used for the parenteral delivery of poorly soluble drugs the original idea of sln was to achieve a controlled release of incorporated drugs by increasing the viscosity of the lipid matrix therefore it is not surprising that in original model, sln is being described as frozen emulsions see fig , left and middle, however, lipids are known to crystallize very frequently in anisotropic platelet shapes and anisotropic sjostrom et al described in that the particle shape of cholesterylacetate sln did strongly gangrene after penicillin depend on the emulsifier platelet shaped particles have been detected for lecithin stabilized particles, while pegsorbitanmonolaurate stabilized particles preserved their spherical shape anisotropic particles have been found in numerous other sln dispersions based on the experimental results, a platelet shaped sln model can be proposed as an alternative see fig , right in the year , westesen questioned the frozen emulsion droplet model with the following statement careful physicochemical characterization has demonstrated that these lipidbased nanosuspensions solid lipid nanoparticles are not just emulsions with solidified droplets nanoemulsionsln frozen emulsion droplet sln platelet shaped particles fig general structure of a nanoemulsion left, and proposed models for sln frozen emulsion droplet model middle and platelet shaped sln model right � core liquid lipid oil � core solid lipid h shell stabilizer during the development process of these systems, interesting phenomena have been observed, such as gel formation on solidification and upon storage, unexpected dynamics of polymorphic transitions, extensive annealing of nanocrystals over significant periods of time, stepwise melting of particle fractions in the lowernanometersize range, drug expulsion from the carrier particles on crystallization and upon storage, and extensive supercooling her comment highlights the complex behavior and changes of sln dispersions in addition, the presence of competing colloidal structures eg micelles, liposomes, mixed micelles, nanodispersed liquid crystalline gangrene after penicillin phases, supercooled melts and drugnanoparticles should be considered additional colloids might have an impact on very different aspects, including the correct measurement of particle size, drug incorporation and toxicity a recent study shows that the cell toxicity of the sln dispersion was reduced by dialysis due to the removal of water soluble components nanostructured lipid carriers nlc nanostructured lipid carriers nlc have been recently proposed as a new sln generation with improved characteristics the general idea behind the system is to improve the poor drug loading capacity of sln by mixing solid lipids with spatially incompatible lipids leading to special structures of the lipid matrix, while still preserving controlled release features of the particles three different types of nlc have been proposed nlc i the imperfect structured type, nlc ii the structureless type and nlc iii the multiple type unfortunately, these structural proposals have not been supported by experimental data they assume a spherical shape and they are not compatible with lipid platelet structures for example, nlc iii structures should contain small oily droplets in a solid lipid sphere fig , left detailed analytical examination of nlc systems by jores et al demonstrate that nanospoon structures are formed, in which the liquid oil adheres on the solid surface of a lipid platelet fig , right gangrene after penicillin jores et al did conclude that neither sln nor nlc lipid nanoparticles showed any advantage with respect to incorporation rate or retarded accessibility to the drug, compared with conventional nanoemulsions the experimental data concludes that nlcs are not spherical solid lipid particles with embedded liquid liquid lipid oil ol d lipid � stabilizer fig proposed nlc iii structure moaified after and experimental determined nanospoon structure described by jores et al side view of particle droplets, but rather, they are solid platelets with oil present between the solid platelet and the surfactant layer very similar structures have been found on q loaded sln by bunjes et al drug localization and release proposed advantages of sln, compared with nanoemulsions, include increased protection capacity against drug degradation and controlled release possibilities due to the solid lipid matrix the general low capacity of crystalline structures to accommodate foreign molecules is a strong argument against the proposed rewards it is therefore necessary to distinguish between drug association and drug incorporation drug association means that the drug is associated with the lipid, but it might be localized in the surfactant layer or between the solid lipid and the surfactant layer similar to the oil in fig , right drug incorporation would mean the distribution of the drug within the lipid gangrene after penicillin matrix another limiting aspect comes from the fact that the platelet structure of sln, which is found in many systems, leads to a tremendous increase in surface area and the shortening of the diffusion lengths furthermore, additional colloid structures present in the sample are alternatives for drug localization the sln for drug incorporation as it was pointed out by westesen the estimation of drug distribution is difficult for dispersions consisting of more than one type of colloidal particle depending on the type of stabilizer and on the concentration ratio of stabilizer to matrix material significant numbers of particles such as liposomes andor mixed micelles may coexist with the expected type of particles the detailed investigation of drug localization is very difficult and only a few studies exist parelectric spectroscopy has been used to investigate the localization of glucocorticoids the results indicate that the drug molecules are attached to the particle surface, but not incorporated into the lipid matrix with betamethasonva lerate, the loading capacity of the particle surface was clearly below the usual concentration of lukowski used energy dispersive xray analysis and found that the drug triamcinolone, dexamethasone and chloramphenicol are partially stored at the surface of the individual nanoparticles the importance of the emulsifier is reflected in a study from danish scientists gangrene after penicillin they produced gammacyhalothrin gch loaded lipid micro and nanoparticles gch had only limited solubility in the solid lipid and was expulsed during storage the appearance of gch crystals was strongly dependent from the solubility of the gch in the emulsifier solutions emulsifier with high gch solubility provoked rapid crystal growth this observation is in accordance with a mechanism of crystal growth according to ostwald ripening slovenian scientist found that ascor bylpalmitate was more resistant against oxidation in nonhydrogenated soybean lecithin liposomes, compared with sln it shows that liposomes might have a higher protection capacity compared with sln fluorescence and esr studies have been used by jores et al to monitor the microenvironment and the mobility of model drugs the results indicate that even highly lipophilic compounds are pushed into a polar environment during lipid crystallization therefore, the incorporation capacity of sln is very poor for most molecules a nitroxide reduction assay gave results in accordance with the results of the distribution compared with nanoemulsions, nitroxides were more accessible in sln and nlc to ascorbic acid, localized in the aqueous environment therefore, nanoemulsions were more protective than sln and nlc systems drug release from sln and nlc could be either controlled by the diffusion of the drug or the erosion of the matrix gangrene after penicillin the original idea was to achieve a controlled release of sln due to the slowing down of drug diffusion to the particle surface this idea is, however, questionable due to drug expulsion during lipid crystallization in addition, very short diffusion lengths in nanoscaled delivery systems lead to short diffusion times, even in highly viscous or solid matrices in most cases, the delivery of the drug will be controlled by the slow dissolution rate in the aqueous environment drug release rate will be highly dependent on the presence of further solubilizing colloids eg micelles, which are able to work as a shuttle for the drug and the presence or absence of a suitable acceptor compartment many investigators studied only the release in buffer media a controlled release pattern under such conditions is not surprising, as it is caused by low solubilization kinetics due to the poor solubility of the drug in vivo, acceptor compartments will be present eg lipoproteins, membranes and will speed up release processes significantly whenever possible, drug loaded sln should be compared with nanosuspensions to separate the general features of the drug and the influence of the lipid matrix results by kristl et al indicate that lipophilic nitroxides diffuse between sln and liposomes the diffusion kinetics was strongly dependent on the gangrene after penicillin nitroxide structure in contrast, uptake of nitroxides in cells was similar between lipophilic nitroxides, suggesting endocytosis as the main mechanism the detailed mechanisms of drug release in vivo are poorly understood in vitro data by olbrich demonstrate that sln are degraded by lipases, degradation by lipase depends on the lipid and strongly on the surfactant steric stabilization eg by poloxamer of sln and nlc are less accessible because lipase needs an interface for activation it is also known that highly crystalline lipids are poorly degraded by lipase administration routes and in vivo data sln and nlc can be administrated at different routes, including peroral, dermal, intravenously and pulmonal peroral administration of sln could enhance the drug absorption and modify the absorption kinetics despite the fact that in most of the sln, the drug will be associated but not incorporated in the lipid, sln might have advantages due to enhanced lymphatic uptake, enhanced bioadhesion or increased drug solubilization by sln lipolysis products such as fatty acids and monoglyc erides a serious challenge represents the preservation of the colloidal particle in the stomach, where low ph values and high ionic strengths favor agglomeration and particle growth zimmermann and muller studied the stability of different sln formulations in artificial gastric juice the main findings of this gangrene after penicillin study are that i some sln dispersions preserve their particle size under acidic conditions, and ii there is no general lipid and surfactant which are superior to others the particular interactions between lipid and stabilizer are determining the robustness of the formulation therefore, the suitable combination of ingredients has to be determined on a case by case basis several animal studies show increased absorption of poorly soluble drugs the efficacy of orally administrated triptolide free drug and triptolide loaded sln have compared in the carrageenaninduced rat paw edema by mei et � their results suggest that sln can enhance the anti inflammatory activity of triptolide and decrease triptolideinduced hepatotoxicity the usefulness of sln to increase the absorption of the poorly soluble drug alltrans retinoic acid has been shown by hu et al on rats gascos group investigated the uptake and distribution of tobramycin loaded sln in rats they observed an increased uptake into the lymph, which causes prolonged drug residence times in the body of the animals furthermore, auc and clearance rates did depend on the drug load the same group described also enhanced absorption of idarubicinloaded solid lipid nanoparticles idasln, in comparison to the drug solution furthermore, the authors described that sln were able to pass the bloodbrain barrier and concluded gangrene after penicillin that duodenal administration of idasln modifies the pharmacokinetics and tissue distribution of idarubicin parenteral administration of sln is of great interest too to avoid the rapid uptake of the sln by the res system, stealth sln particles have been developed by the adoption of the stealth concept from liposomes and polymer nanoparticles reports indicate that doxorubicin loaded stealth sln circulate for long period of time in the blood and change the tissue distribution therefore, sln could be alternatives to marketed stealthliposomes, which can decrease the heart toxicity of this drug due to changed biodistribution long circulation times have also been observed for poloxamer stabilized sln with paclitaxel the dermal application is of particular interest and it might become the main application of sln sln pose occlusive properties which are related to the solid structure of the lipid human in vivo results of the group of muller demonstrate that sln can improve skin hydration and viscoelasticity sln have also uv protection capacity due to their reflection of uv light furthermore, data by schaferkorting suggest sln can be used to decrease drug side effects due to sln mediated drug targeting to particular skin layers further reports describe additional applications of sln as well as gene delivery, delivery to the eye, pulmonary delivery, and drug targeting gangrene after penicillin of anticancer drugs studies of the different groups also propose the use of sln for brain targeting to deliver mri contrast agents or antitumour drugs summary and outlook sln and nlc are now investigated by many scientists worldwide in contradiction to early proposals, they certainly do not combine all the advantages of the other colloidal drug carriers and avoid the disadvantages of them sln are complex colloidal dispersions, not just frozen emulsions sln dispersions are very susceptible to the sample history and storage conditions disadvantages of sln include gel formation on solidification and upon storage, unexpected dynamics of polymorphic transitions, extensive annealing of nanocrystals over significant periods of time, stepwise melting of particle fractions in the lowernanometersize range, drug expulsion from the carrier particles on crystallization and upon storage, and extensive supercooling the anisotropic shape of many sln dispersions increases the surface area significantly, decreases the diffusion lengths to the surface and changes the rheological behavior dramatically eg gel formation furthermore, the presence of alternative colloidal structures micelles, liposomes has to be considered to contribute to drug localization in most cases, the drug will be associated with the lipid and not incorporated studies demonstrate that sln and nlc might have no advantages compared with submicron emulsions, in regard to protection from the aqueous gangrene after penicillin environment on the other side, animal data suggest that sln can change the pharmacokinetics and the toxicity of drugs in many cases, drug incorporation might not be required and drug association with the lipid can be sufficient for lymphatic uptake clearly, more detailed studies are necessary to get a deeper understanding of the in vivo fate of these carriers whenever possible, sln and nlc systems should be compared directly with alternative colloidal carriers eg liposomes, nanoemulsions, nanosuspensions to evaluate their true potential references eldem t, speiser p and hincal a optimization of spraydried and congealed lipid micropellets and characterization of their surface morphology by scanning electron microscopy pharm res speiser p lipidnanopellets als tragersystem ftir arzneimittel zur peroralen anwendung, european patent ep domb aj lipospheres for controlled delivery of substances united states patent no domb aj long acting injectable oxytetracyclineliposphere formulation int } pharm domb aj liposphere parenteral delivery system proc intl symp control rel bioact mater siekmann � and westesen � submicronsized parenetral carrier systems based on solid lipids, pharm pharmacol lett miiller rh, lucks js arzneistofftrager aus festen lipidteilchen, feste lipid nanospharen sln european patent no muller rh, mehnert w, lucks js, schwarz c, zur mtihlen a, weyhers h, freitas � and riihl d solid lipid nanoparticles sln � an gangrene after penicillin alternative colloidal carrier system for controolled drug delivery eur j pharm biopharm sjostrom � and bergenstahl � preparation of submicron drug particles in lecithin stabilized ow emulsions i model studies of the precipitation of cholesteryl acetate int} pharm cavalli r, caputo � and gasco mr solid lipospheres of doxorubicin and idaru bicin int} pharm rr gasco mr method for producing solid lipid microspheres having a narrow size distribution united states patent no muller rh pharmazeutische technologie, moderne arzneiformen, wiss verlagsges stuttgart muller rh and runge sa, solid lipid nanoparticles sln for controlled drug delivery, in submicron emulsions in drug targeting and delivery, benita s ed, harwood academic publishers small d handbook of lipids the physical chemistry of lipids from alkanes to phospholipids, plenum press, new york ahlin p, kristl j and smidkobar j optimization of procedure parameters and physical stability of solid lipid nanoparticles in dispersions acta pharm lippacher a, muller rh and mader � investigation on the viscoelastic properties of lipid based colloidal drug carriers int ] pharm zur miihlen a and mehnert w drug release and release mechanism of prednisolone loaded solid lipid nanoparticles pharmazie zur miihlen a, schwarz � and mehnert w solid lipid nanoparticles sln for controlled drug delivery � drug release and release mechanism lander r, manger w, gangrene after penicillin scouloudis m, ku a, davis � and lee a gaulin homogenization a mechanistic study biotechnol prog jahnke s the theory of high pressure homogenization, in emulsions and nanosus pensions for the formulation of poorly soluble drugs, muller rh, benita s and bohm � eds, medpharm scientific publishers stuttgart, pp siekmann � and westesen � melthomogenized solid lipid nanoparticles stabilized by the nonionic surfactant tyloxapol, i preparation and particle size determination pharm pharmacol lett bunjes h, siekmann � and westesen � , emulsions of supercooled melts � a novel drug delivery system, in submicron emulsions in drug targeting and delivery, benita s ed, harwood academic publishers zur miihlen a feste lipidnanopartikel mit prolongierter wirkstofflibera tion herstellung, langzeitstabilitat, charakterisierung, freisetzungsverhalten und machanismen, phd thesis, free university of berlin friedrich i and miillergoymann cc characterization of solidified reverse micellar solutions srms and production development of srmsbased nanosuspensions eur j pharm biopharm siekmann � and westesen � investigations on solid lipid nanoparticles prepared by precipitation in ow emulsions eur } pharm biopharm fessi h, puisieux f, ammoury n and benita s nanocapsule formation by interfacial polymer deposition following solvent displacement int j pharm rr hu fq, yuan h, zhang hh and fang m preparation of solid lipid nanoparticles with clobetasol propionate by a novel solvent diffusion method in gangrene after penicillin aqueous system and physicochemical characterization int j pharm schubert ma and miillergoymann cc solvent injection as a new approach for manufacturing lipid nanoparticles�evaluation of the method and process parameters eur j pharm biopharm danielsson i and lindman � the definition of microemulsion coll surf � gasco mr solid lipid nanospheres from warm microemulsions pharma technol eur boltri l, canal t, esposito pa and carli f lipid nanoparticles evaluation of some critical formulation parameters proc intl symp control rel bioact mater cavalli r, marengo e, rodriguez l and gasco mr effect of some experimental factors on the production process of solid lipid nanoparticles eur j pharm biopharm gasco mr, morel s and carpigno r optimization of the incorporation of des oxycortisone acetate in lipospheres eur f pharm biopharm dahms g and seidel h method for the preparation of solidlipid nanoparticles slns without high pressure homogenizer for pharmaceutical, cosmetic and food applications german patant application de zuidam nj, lee ss, l and crommelin dja sterilization of liposomes by heat treatment pharm res lukyanov an and torchilin vp autoclaving of liposomes j microencap schwarz � and mehnert w sterilization of drugfree and tetracaineloaded solid lipid nanoparticles sln proc st world meeting apgiapv, budapest schwarz �, freitas �, mehnert w and muller rh sterilization and physical gangrene after penicillin stability of drugfree and etomidateloaded solid lipid nanoparticles proc intl symp control rel bioct mater liedtke s, jores k, mehnert w and mader � possibilities of noninvasive physicochemical characterisation of colloidal drug carriers, th intl symp control rel bioact mater vol , controlled release society, paris freitas � feste lipidnanopartikel sln mechanismen der physikalischen destabilisierung und stabilisierung phd thesis, free university of berlin cavalli r, caputo o, carlotti me, trotta m, scarnecchia and gasco mr sterilization and freezedrying of drugfree and drugloaded solid lipid nanoparticles int} pharm heiati h, tawashi r and phillips nc drug retention and stability of solid lipid nanoparticles containuing azidothymidine palmitate after autoclaving, storage and lyophilisation} microencap sculier jp, coune a, brassine c, laduron c, atassi g, ruysschert gm and fruhling j intravenous infusion of high doses of liposomes containing nsc , a water insoluble cytostatic agent a pilot sudy with pharmacokinetic data } clin oncol rupprecht h physikalischchemische grundlagen der gefriertrocknung, in essig d and oschmann r eds, lyophilization paperback apv, band , wis senschaftliche verlagsgesellschaft mbh, stuttgart, pp pikal mj, shah s, roy ml and putman r the secondary drying stage of freeze drying drying kinetics as a function of temperature and chamber pressure intj pharm schwarz � and mehnert w freezedrying of drugfree and drugloaded solid lipid nanoparicles int gangrene after penicillin j pharm crowe lm, crowe jh, rudolph a, womersley � and appel l preservation of freezedried liposomes by trehalose arch biochem biophys siekmann � and westesen � melthomogenized solid lipid nanoparticles stabilized by the nonionic surfactant tyloxapol, ii physicochemical characterization and lyophilisation pharm pharmacol lett zimmermann e, muller rh and mader � influence of different parameters on reconstitution of lyophilized sln int j pharm lim sj, lee mk and kim ck altered chemical and biological activities of alltrans retinoic acid incorporated in solid lipid nanoparticle powders j control rel marengo e, cavalli r, rovero g and gasco mr scaleup and optimization of an evaporative drying process applied to aqueous dispersions of solid lipid nanoparticles pharm dev techn freitas � and muller rh spraydrying of solid lipid nanoparticles sln eur j pharm biopharm laggner p xray diffraction of lipids, in spectral properties of lipids, hamilton rj and cast j eds, sheffield academic press garti n and sato � eds, crystallization and polymorphism of fats and fatty acids, marcel dekker new york and basel sjostrom b, kaplun a, talmon y and cabane � structures of nanoparticles prepared from oil in water emulsions pharm res siekmann � and westesen � submicron sized parenteral carrier systems based on solid lipid, pharma pharmacol lett illing a, unruh t gangrene after penicillin and koch mhj investigation on particle selfassembly in solid lipidbased colloidal drug carrier systems pharm res jores k, mehnert w, drechsler m, bunjes h, johann � and mader � investigations on the structure of solid lipid nanoparticles sln and oilloaded solid lipid nanoparticles by photon correlation spectroscopy, fieldflow fractionation and transmission electron microscopy } control rel jores k, mehnert w and mader � physicochemical investigations on solid lipid nanoparticles sln and on oilloaded solid lipid nanoparticles a nmr and esr study pharm res zur mtihlen a, zur miihlen e, niehus h and mehnert w atomic force microscopy studies of solid lipid nanoparticles pharm res dingier a, blum rp, niehus h, mtiller rh and gohla s solid lipid nanoparticles slnlipopearls � a pharmaceutical and cosmetic carrier for the application of vitamin e in dermal products j microencap mtiller rh zetapotential und partikelladung kurze theorie, praktische mefi durchfuhrung, dateninterpretation, wissenschaftliche verlagsgesellschaft stuttgart lai sl, guo jy, petrova v, ramanath g and allen lh sizedependent melting properties of small tin particles nanocalorimetric measurements phys rev lett westesen k, siekmann � and koch mhj investigations on the physical state of lipid nanoparticles by synchrotron radiation xray diffraction int} pharm westesen � and bunjes h do nanoparticles prepared from lipids solid at room temperature always possess a solid matrix?