Microemulsions are often defined as thermodynam- ically stable liquid solutions; their stability is a consequence of the ultralow inter- facial tension between the oil and water phases buy discount super cialis 80 mg online erectile dysfunction doctor montreal. The latter are thermodynamically unstable cheap super cialis american express strongest erectile dysfunction pills, the droplets of their dispersed phase are generally larger than 0. Microemulsions exhibit several properties that are of particular interest in pharmacy: r Their thermodynamic stability enables the system to self-emulsify, the properties not being dependent on the followed process. Such a small size yields a very large interfacial area, from which the drug can be quickly released into the external phase when in vitro or in vivo absorption takes place. In Vivo Evaluations of Solid Lipid Nanoparticles and Microemulsions 233 r The technology required to prepare microemulsions is simple, because their ther- modynamic stability means that no significant energy contribution is required. The limits in the use of microemulsions in the pharmaceutical field derive, chiefly, from the need for all components to be acceptable, particularly surfactants and cosurfactants. The amounts of surfactants and cosurfactants required to form microemulsions are usually higher than those required for emulsions. Microemulsions offer several advantages for pharmaceutical use, such as ease of preparation, long-term stability, high solubilization capacity for hydrophilic and lipophilic drugs, and improved drug delivery. They can also be used in oral and par- enteral delivery (54), but this review is limited to in vivo studies by the transdermal route (55). A microemulsion carrying methylnicotinate was prepared using lecithin, water, and isopropylmiristate (56) and was applied onto the skin of human vol- unteers; appreciable transport of the bioactive substance was obtained. An o/w microemulsion and an amphiphilic cream, both carrying curcumin, were applied onto the skin of human volunteers; curcumin was chosen as model drug to compare the stratum corneum penetration of the two formulations. A deeper part of the stratum corneum was found to be accessible to the microemul- sion than to the cream (57). Niflumic acid was incorporated in a sugar-based sur- factant and tested in humans (58). It was found that the microemulsion formulation saturated with the drug (1%) was as efficient as a commercially available 3% o/w emulsion. Good human skin tolerability of a lecithin-based o/w microemulsion com- pared with a conventional vehicle (o/w, w/o, and gel) was reported (59). However, the amount that emulsions permeated from the microemulsion was sevenfold that from the gel, although the concentration of azelaic acid in the microemulsion was less than half. The thickened microemulsion was then applied to lentigo maligna (61) and confirmed the efficacy of azelaic acid to treat this variety of melanoma; the microemulsion led to the regression of the lesions. Comparison between this treatment and treatment with a cream (20% azelaic acid and 3% sal- icylic acid) showed that the microemulsion led to regression earlier than did the cream. Ten cases were treated; the average time for the complete remission was halved compared with the times required with the cream. Microemulsions for Transdermal Application of Apomorphin Apomorphine, a potent, short-acting dopamine agonist at D1 and D2 dopamine receptors, potentially represents a very useful adjunctive medication for patients with Parkinson’s disease. However, its clinical use is significantly limited by its pharmacokinetic profile characterized by a short half-life (approximately 30 min- utes), rapid clearance from plasma, absence of storage or retention in brain regions, poor oral bioavailability (5%), and first-pass hepatic metabolism. Several, unsuc- cessful attempts have been made to overcome these limits by using other routes of administration, but at present, its use remains limited to few clinical conditions. Recently, apomorphine was incorporated into microemulsions to study whether they are a feasible vehicle for transdermal transport of this drug. In the preparatory in vitro study (62), two different microemulsions whose components were all biocompatible were studied; the concentration of apomorphine was 3. Since apomorphine is highly hydrophilic, apomorphine–octanoic acid ion pairs were synthesized to increase its lipophilicity. The flux of drug from the two thick- ened microemulsions through hairless mouse skin was respectively 100 g/(h cm2) and 88 g/(h cm2). The first formulation, having the higher flux, was chosen for in vivo administration in patients with Parkinson’s disease. For the in vivo study, 21 patients with idiopathic Parkinson’s disease who pre- sented long-term l-dopa syndrome, motor fluctuation, and prolonged “off” peri- ods were selected (63). In these conditions, a single layer of microemulsion (1 mm thick) was directly in contact with the skin surface and acted as a reservoir of apomorphine. In all patients except two, apomorphine was detected in blood samples after a variable lag time. Pharmacokinetic analysis revealed that epicutaneous–transdermal apo- morphine absorption was rapid (mean half-life of absorption = 1. This result is in contrast with other reports, in which the transdermal route did not produce detectable plasma levels of apomorphine, or in which no apomorphine was trans- ported passively through the skin (64,65). Probably, this difference was mainly due to the peculiar pharmaceutical preparation used. Pharmacokinetic analysis confirmed the absorp- tion of apomorphine and the maintenance of therapeutic plasma levels for several hours (mean Cmax = 31. Results of in vivo experiments in laboratory animals and humans are very encouraging: efficient drug protection, cell internalization, controlled release, and passage through biological anatomical barriers have been achieved. Plasma protein adsorption patterns on emulsions for parenteral administration: establishment of a protocol for two-dimensional polyacrylamide elec- trophoresis. Analysis of plasma protein adsorption on polymeric nanoparticles with different surface characteristics. Atovaquone nanosuspensions show excellent ther- apeutic effect in a new murine model of reactivated toxoplasmosis. Pharmacokinetics, tissue distribution and bioavailability of clozapine solid lipid nanoparticles after intravenous and intraduodenal administra- tion. Pharmacokinetics, tissue distribution and bioavailability of nitrendipine solid nanoparticles after intravenous and intraduodenal administration. Transferrin conjugate solid lipid nanoparticles for enhanced delivery of quinine dihydrochloride to the brain. Nanoparticle surface charges alter blood- brain barrier integrity and permeability. Body distribution of camptothecin solid lipid nanoparticles after oral administration. Etoposide -incorporated tripalmitin nanopar- ticles with different surface charge; formulation, characterization, radiolabeling, and biodistribution studies. Enhanced brain targeting by synthesis of 3 ,5 -dioctanoyl- 5-fluoro-2 -deoxyuridine and incorporation into solid lipid nanoparticles. Injectable actarit loaded solid lipid nanoparticles as passive targeting therapeutic agents for rheumatoid arthritis. Solid lipid nanoparticles formed by solvent in water emulsion technique: Development and influence on insulin stability. Lung-targeting delivery of dexamethasone acetate loaded solid lipid nanoparticles. Incorporation of cyclosporin A in solid lipid nanoparti- cles in solid lipid nanoparticles.

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Terminologies used (nm) References Polymeric systems 1 Dendrimers 1–10 1 generic 80mg super cialis visa erectile dysfunction freedom book,5 2 Polymer micelles 10–100 1 3 Niosomes 10–150 1 4 Nanoparticles 50–500 1 generic super cialis 80 mg with mastercard discount erectile dysfunction drugs,6–10 5 Nanocapsules 100–300 1,11,12 6 Nanogels 200–800 1 7 Polymer–drug nanoconjugates 1–15 13–16 8 Chitosan polymers 100–800 17,18 9 Methacrylate polymers 100–800 19 Lipid systems 1 Solid lipid nanoparticles 50–400 20 2 Lipid nanostructured systems 200–800 21 3 Cubosomes 50–700 1 4 Liposomes 10–1000 22 5 Polymerosomes 100–300 13 6 Immunoliposomes 100–150 13 Protein/peptide nanotubes 1 Peptide nanotubes 1–100 23 2 Fusion proteins and immunotoxins 3–15 13 Metal nanostructures 1 Metal colloids 1–50 1,9 2 Carbon nanotubes 1–10 (diameter) 1 and 1–1000 (length) 3 Fullerene 1–10 1 4 Gold nanoparticles 100–200 13,24 5 Gold nanoshells 10–130 13 6 Silicone nanoparticles 25 7 Magnetic colloids 100–600 26 when used as drug carriers. Owing to this property, these can be used for deliv- ering different drug molecules. As these protein molecules are biocompatible and biodegradable, this is a distinct advantage over their synthetic counterparts. Some of the natural organic and protein molecules are also described as carriers for drug. These are fabricated as nanoparticles or nanofibers for delivering the drugs (29–31). Gregory Gregoriadis in 1974 (32) lead to several breakthrough discoveries by using nanoparticles as drug carriers resulting from cutting-edge researches based on multidisciplinary approaches, many more applications have developed. We have 4 Pathak discussed in detail about the nanoparticulate drug delivery systems in our first vol- ume in chapters 1 and 13, which covered most of the development and technologies and applications till 2005. Several research reports have been published on the applications of nanoparticulate drug delivery systems using various drug entities and polymers and different forms of drug delivery systems. The employment of poly(butyl cyanoacrylate) nanoparticles showed high efficacy of nanoparticle-bound doxoru- bicin in intracranial glioblastoma in rats. An interest- ing review on the application of nanotechnology in breast cancer therapy is covered by Tanaka et al. More than 150 clinical trials are being conducted worldwide for the treat- ment of breast cancer by using nanotechnology-based products. This review covers different generations of nanotechnology tools used for drug delivery, especially in breast cancer. Injectable drug delivery nanovectors are used for cancer therapy, especially when multiple-drug therapy is used. These vectors need to be large enough to evade the body defense but should be sufficiently small to avoid blockages in even the capillaries. As these vectors are smaller than the diameters of the capillaries, the blockages can be effectively prevented (13). These nanovectors can functionalize in order to actively bind to specific sites and cells after extravasation thorough ligand–receptor interactions. To maximize the specificity, a surface marker (receptor or antibody) should be overexpressed on target cells relative to normal ones. Another area that is being explored is to use the external energy or the environmental system to release cytotoxic drugs at the site of action by using metabolic markers or acidity levels that accompany inflammatory states, infections, and neoplastic processes (13). Nanosized vectors include fusion proteins and immunotoxins/polymers, dendrimers, polymer–drug conjugates, polymeric micelles, polymerosomes and liposomes, and metal nanopar- ticles such as gold nanoparticles or nanoshells. The major concern of nanovec- tors based on polymers is their biocompatibility, biodegradability, and release of drug from the polymer nanosystem in the body at the site of action. In case of lipid-based systems, the problems of biocompatibility and biodegradability are not Recent Developments in Nanoparticulate Drug Delivery Systems 5 6 Pathak Recent Developments in Nanoparticulate Drug Delivery Systems 7 encountered. Liposomes, either single layered or multilayered, have shown signif- icant potential as nanovectors for cancer treatment. They have shown preferential accumulation in tumor via enhanced permeability and retention effect. However, too long circulating liposomes may lead to extravasation of the drug into undesired sites. Long circulating half-life, soluble or colloidal behavior, high binding affinity, biocompatibility, easy functionalization, easy intracellular penetration, controlled pharmacokinetic, and high drug protection are all characteristics simultaneously required for an optimal nanocarrier design and efficient applications. Pugna has shown in his article that controlling adhesion in highly flexible nanovectors can help in smartly deliv- ering the drug (13). The high flexibility of nanovectors is used to release the drug only during adhesion by nanopumping, and, as a limit case, by the new concept of adhesion-induced nanovector implosion. He recommended that fast pumping and slow diffusion of drug could thus be separately controlled. The resultant nanoshells were sized around 110 nm, and they incorporated paclitaxel in the oil phase. They have shown that such a nanoshell delivery system can be used for different hydrophobic oil-soluble drugs. They reported that paclitaxel could be effectively released from biodegradable poly(lactic-glycolic acid) nanoparticle delivery system, while maintaining potent, combined, cytotoxic, and radio-sensitizing abilities for hypoxic human breast tumor cells. However, they could not elucidate the mechanism of transport of these nanoparticles. Several other studies have shown the application of nanoparticulate drug delivery systems in cancer treatment (70–74). Antibody targeting of drug substances can improve the therapeutic efficacy of the drug substance, as well as improve the distribution and concentration of the drug at the targeted site of drug action. The development of compounds that enhance immune responses to recombinant or synthetic epitopes is of considerable importance in vaccine research. This study compared lipid nanoparticles with nanostruc- tured lipid carriers composed of precirol and squalene, a liquid lipid. They showed that the particle size was between 200 and 300 nm for both the carriers. Their results showed that the entrapment of 8-methoxypsoralen in nanoparticulate systems could minimize the permeation dif- ferentiation between normal and hyperproliferative skin compared with that of free drug in aqueous control (20). Juliano has written a very good article about the challenges in macromolecular drug delivery and the use of various techniques including poly- meric carriers for the macromolecular drugs (77). This is probably one of the first of its kind of research report on quality by design Recent Developments in Nanoparticulate Drug Delivery Systems 9 in the field of pharmaceutical nanotechnology. They used near infrared and chemo- metric analysis and several other well-known processes for the characterization of emulsions during processing. To develop a functional device for tumor imag- ing, they embedded quantum dots within hydrogel nanoparticles. Their results sug- gest that the derivatized quantum dots enhance tumor monitoring through quan- tum dot imaging and that they are useful in cancer monitoring and chemotherapy. They showed different levels of drug release profiles based on varying polymer cross-linking. This is the first report giving information on the new technique by using the nanotube and the antibody cancer cell detection system. This review extensively covers various aspects of nanodrug delivery systems and their uptake in biological system at cellular levels. They have discussed in detail the applications of various nanosystems and their interactions at cellular levels and the mechanism for the uptake of the nanosys- tems (2). With many examples, they have shown that nanoparticulate drug delivery systems show a promising approach to obtain desirable delivery properties by altering the biopharmaceutic and pharmacokinetic properties of the molecule. A detailed description on micro (nano) emulsions has been recently discussed in a review by Gupta and Moulik (88). It covered the devel- opment and characterization of biocompatible micro (nano) emulsion systems and their evaluation as probable vehicle for encapsulation, stabilization, and delivery of bioactive natural products and prescription drugs.

Z. Derek. Spring Hill College.