Sandimmun Neoral

Azathioprine (Imuran) Basiliximab (Simulect) Cyclosporine, oral (Sandimmune, Neoral, Gengraf)... 

Keown, P, and D. Niese, Cyclosporine microemulsion increases drug exposure and reduces acute rejection without incremental toxicity in de novo renal transplantation. International Sandimmun Neoral Study Group. Kidney Int, 1998. 54(3) 938-44. 

Bistrup C, Nielsen FT, Jeppesen UE, Dieperink H. Effect of grapefruit juice on Sandimmun Neoral absorption among stable renal allograft recipients. Nephrol Dial Transplant 2001 16(2) 373-377. 

Parenteral 2 mg/mL in 50 mL vials Cyclosporine (Sandimmune, Neoral, SangCya)... 

The new cyclosporine formulation (Sandimmun Neoral, Novartis Pharmaceuticals Corporation, East Hanover, NJ) is a self-microemulsifying drug delivery system, which consists of the drug in a lipophilic solvent (corn oil), hydrophilic cosolvent (propylene glycol) surfactant and an antioxidant [37]. Upon contact with GI fluids, Sandimmun Neoral readily forms a homogenous, monophasic microemulsion, which allows the absorption of the drug molecules. Unlike Sandimmun, the formation of this microemulsion is independent of bile salt activity, and indeed, studies have shown that the absorption of cyclosporine from the new formulation is much less dependent on bile flow [38] and is unaffected by food intake [39],... 

Vonderscher, J., and A. Meinzer, 1994. Rationale for the development of Sandimmune Neoral. 

The most recent development (in terms of physicochemical/particle size approaches) in the design of lipid-based delivery systems has been the use of microemulsions, microemulsion preconcentrates, or self-microemulsifying drug delivery systems (SMEDDS), typified by the Sandimmun Neoral formulation. 

The current proprietary cyclosporin formulation, Sandimmun Neoral, is a microemulsion formulation. Although the formulation details of the Neoral formulation are not generally available, the relative bioavailabilities of the Neoral formulation and the initial Sandimmun formulation have been reported. In a dose linearity study, the relative bioavailability of the Neoral formulation compared with the Sandimmun formulation varied from 1.74 at a 200-mg dose to 2.39 at an 800-mg dose, illustrating the usefulness of the microemulsion formulation and suggesting an approximate twofold increase in bioavailability from the microemulsion formulation [74], Further studies showed that the absorption of cyclosporin from the Neoral formulation was significantly less variable [75] and less dependent on bile flow [76] than oral Sandimmun and that its absorption was unaffected by food [77], In terms of its apparent lack of reliance on bile for absorption, it is not known whether cyclosporin is absorbed from the formulation directly or just requires much lower bile salt concentrations to facilitate absorption. 

In contrast, data from a recent conference presentation by Choc and Robinson [100], indicated that cyclosporin metabolite ratios were similar after oral administration of either Sandimmun or the Neoral formulation, suggesting minimal changes in cyclosporin first-pass metabolism after Neoral administration. Furthermore, Neoral/Sandimmun area under the curve (AUC) ratios were similar (approximately 2) after cyclosporin administration in either the absence or presence of a CYP3A/P-gp inhibitor, whereas an AUC ratio of approximately 1 would have been expected if bioavailability was limited by metabolism or antitransport. However, these data have not yet been published, and the relative contributions of enhanced absorption or reduced metabolism in the CY bioavailability enhancement provided by Sandimmun Neoral are yet to be fully defined. 

Some studies reported that polyoxyethylene (POE) stearates (under the brand name Myrj) and alkyl-polyethyleneoxide (PEO) surfactants (under the brand name Brij) can inhibit efflux pumps. The oral bioavailability of the P-gp substrate cyclosporine A administered in a solid dispersion of polyoxyethylene 40 stearate (Myrj 52) was in the same range as the oral bioavailability of the commercial product Sandimmune Neoral (Liu et al. 2006). In a study by Lo, it has been shown that apical to basolateral epirubicin transport across Caco-2 cells was enhanced in the presence of polyoxyethylene 40 stearate and the basolateral to apical transport was decreased. These results indicate that polyoxyethylene stearates effect efflux pumps (Lo 2003). Similar results were gained when using polyoxyethylene laurylether (Brij 30). In another study, tablets based on polyoxyethylene 40 stearate containing the P-gp substrate rhodamine 123 increased the oral bioavailability in rats by about 2.4-fold (Foger et al. 2006a). 

R.P. Scherersol system Liquid formulations for softgels, which incorporates the drug in a microemulsion preconcentrate or microemulsion form. Oral delivery of proteins and peptides enhanced oral bioavailability with reduced inter- and intraindividual variability in pharmacokinetics of certain drugs. Sandimmune Neoral (cyclosporine). 

Unfortunately, the number of commercial formulations is very limited, primarily because of stability and manufacturing problems encountered during large-scale production. The list includes Sandimmune Neoral (cyclosporine A Novartis AG, Switzerland), which contains a microemulsion preconcentrate and is available as soft gels and solutions. Sandimmune (cyclosporine A Novartis AG, Switzerland), which contains an emulsion preconcentrate, and lipid soluble vitamins. Both formulations of cyclosporine have self-emulsifying properties and spontaneously form an o/w microemulsion (particle size <0.15 pm) and an o/w emulsion, respectively in the aqueous fluids of the GI tract. Although the discussion concerning potential of liposomes, niosomes, microemulsions, and solid dispersions for oral delivery is outside the scope of this chapter, the interested reader is referred to recently published reviews on these topics. " ... 

A formulation of ciclosporin (Sandimmun Neoral, Novartis) incorporates the drug in a preconcentrate which forms a microemulsion on dilution in aqueous fluids. This formulation offers an alternative to the oil formulation of ciclosporin (Sandimmun) which in vivo would be emulsified by bile salts and pancreatic enzymes. The residence time of ciclosporin in the gastrointestinal tract is shorter and the rate of absorption is faster with the microemulsion formulation (Fig. 7.19). 

Micelle Formulations A micelle system can be either water-based or oil-based. The use of a micelle formulation for poorly water-soluble drugs for systemic delivery has been well recognized. In recent years, the effective development of self-emulsifying microemulsions or mixed micelle-based lipid formulations products, such as Sandimmun Neoral (cyclosporin), Norvir (ritonavir), and Fortovase (saquinavir), has substantially increased interest in the application of lipid-based micelle formulation to improve oral delivery of poorly water-soluble drugs as well as protein and peptide drugs.51... 

CDC are defined only by their size (most scientists agree on sizes below 1 pm others set 0.5 pm as the upper limit). CDC are very heterogeneous in all other aspects (e.g., thermodynamic stability, chemical composition, and the physical state, including solid, liquid, or liquid-crystalline dispersions) [ 1 ]. The most prominent examples are nanoparticles, nanoemulsions, nanocapsules, liposomes, nanosuspensions, (mixed) micelles, microemulsions, and cubosomes. Some CDC have reached the commercial market. Probably the best known example is the microemulsion preconcentrate of cyclosporine (Sandimmun-Neoral), which minimized the high variability of pharmacokinetics of the Sandimmun formulation. In addition, intravenous injectable CDC have been on the commercial market for many years. Examples include nanoemulsions of etomidate (Etomidat-Lipuro) and diazepam (Diazepam-Lipuro) [2-4], mixed micelles (Valium-MM, Konakion), and liposomes (AmBisome) [5]. 

Improved oral bioavailability Micro emulsions have shown tremendous potential in improving oral bioavailabihty of an array of therapeutic agents such as simvastatin [8], carvedilol [9] and Cyclosporine A (Sandimmune Neoral) [4]. 

In recent years there has been an increased interest in the utility of lipid-based delivery systems to enhance oral bioavailability (4). It is generally known that membrane permeability is directly correlated to a drug s water-lipid partition coefficient however, the systemic availability of highly lipophilic drugs is impeded by their low aqueous solubility. In an effort to improve this solubility-limited bio-availabiliy,formulators have turned to the use of lipid excipients to solubilize the compounds before oral administration. Several formulations are currently on the market, for example, Sandimmun/Neoral (cyclosporin microemulsion), Norvir (ritonavir), and Fortovase (saquinavir)... 

Cyclosporine, Oral (Sandimmune, Neoral, Gengrcrf) [Immunosuppressanf/Polypepride Anribioric] WARNING f... 

Cyclosporin (Sandimmune, Neoral) 1.2 3-5 Variable 10-20 (shorter in children) Sandimmune IV infusion (1.0) oral (-0.28 [0.1-0.9]) Neoral oral (—34-42 based on comparative AUC data)... 

Once more considering the thermodynamic stability of microemulsions, as well as the fact that the droplet size in microemulsions is frequently much smaller than that of the corresponding emulsion, microemulsions have also been applied as drug vehicles for cyclosporine oral administration (Sandimmune Neoral). In a number of investigations, it was found that the bioavailability of cyclosporine may be further improved with this formulation at the same time as the pharmacokinetic variability is reduced [43-45,47-49]. An example of this type of results is given in Fig. 6. In line with the findings of Tarr and Yalkowsky [46] on the effect of droplet size on the absorption from emulsions, these results seem to indicate that one contribution to the enhanced absorption from the microemulsion formulation is the small droplet size in this system. However, as shown... 

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