Neoral cyclosporine, oral

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

Cyclosporine Neoral, Sandimmune Oral 2.5 mg/kg body weight per day can be increased after 8 wk by 0.5-0.75 mg/kg body weight per day dose can be increased after another 4 weeks to a maximum daily dose of 4 mg/kg body weight per day. May cause nephrotoxicity and gastrointestinal problems. 

Lipovenos Fresenius Neoral Cyclosporin A Novartis Oral... 

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. " ... 

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... 

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... 

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... 

NEORAL (Novartis) (cyclosporine capsules, oral solution, USP) March 2004 labeling... 

Cyclosporine A absorption was evaluated following oral administration of the regular Sandimmun soft gelatin capsule and the Neoral microemulsion formulation to patients with psoriasis. The Neoral formulation showed 32% increased mean AUC value, increased Cmax, decreased tmax and reduced variability between patients (Figure 6.4) [42],... 

FIGURE 6.4 Individual plasma cyclosporine A profiles following oral administration of Neoral microemulsion formulation (a) and the regular Sandimmun soft gelatin capsule (b) in psoriasis patients. (From Erkko, P., et al., Br. J. Dermatol., 136, 82, 1997. With permission.)... 

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). 

Propylene glycol, 42% ethanol, glycerin, Gremophor RH 40, peppermint oil, water. 11.9% Ethanol, dl-Q -tocopherol, corn oil-mono-di-triglycerides, Gremophor RH 40, propylene glycol. Kaletra oral solution (Lopinavir and ritonavir) Neoral oral solution (Cyclosporin A)... 

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]. 

Oral cyclosporine is less effective as maintenance therapy in IBD, perhaps because of its limited intestinal absorption. In this setting, long-term therapy with NEORAL (a microemulsion formu-... 

After oral administration of cyclosporine (as neoral), the time to peak blood concentrations is... 

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)... 

There are a few marketed drug delivery systems containing microemulsions that are related to the lipid systems we describe here. Sandimmune Neoral (Novartis, Switzerland) [17], which delivers the lipophilic peptide cyclosporin A, is based on medium-chain triglycerides obtained from coconut oil, a semisynthetic emulsifier (ricinoleate), and propylene glycol. The absorption of the drug taken orally as a microemulsion increases dramatically compared to that of an aqueous suspension [17]. Another marketed example, in which Cs/Cio triglycerides from coconut oil are used, is a soft gelatin capsule of vitamin D3 [18]. 

It is well known, that the co-administration of poorly water soluble drugs with a meal rich in fat can enhance the oral bioavailability of poorly water soluble drugs and lipid based delivery systems mostly based on complex lipid mixtures are intensively studied to enhance the bioavailability of poorly water soluble drugs. ° ° A couple of lipid based formulations are already on the market, e.g. for cyclosporine (Neoral ), retonavir (Norvir ), saquinavir (Fortovase ) and amprenavir (Agenerase ). Formulations of solid lipid nanoparticles may present a further alternative for oral delivery of poorly water soluble drugs as well as for proteins and peptides with low oral bioavailability due to degradation in the intestinal fluids. ... 

The oral bioavailability of cyclosporine in dependence on the formulation (SLN, nanocrystals and Sandimmun Neoral ) was investigated in pigs by Muller et The cyclosporine blood curve after administration of Sandimmun Neoral ) showed a plasma peak after about 2 h with a slow but steady decay of the plasma concentration afterwards. The administration of cyclosporine loaded in SLN led to a lower AUC (7964 vs. 9396 ng h/ml for SLN and Sandimmun Neoral but similar time period of therapeutic concentrations. As no high initial plasma peak was observed after administration of the SLN formulation, cmax 950 VS. 1561 ng/ml for SLN and Sandimmun Neoral ) the potential nephrotoxicity of the drug may be reduced for the SLN formulation. The administration of drug nanocrystals did not lead to a sufficient plasma concentration the blood concentrations were between 30 and 70 ng/ml over a period of 14 h. 

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