Oral cyclosporin formulations

#1. Field of the Invention

#The field of this invention is oral cyclosporin formulations.

#2. Background

#FIG. 1 provides the cyclosporin peak concentration (C.sub.max) achieved in rats for several oral formulations according to the subject invention, where the C.sub.max is shown as a relative value compared to the C.sub.max achieved with SANDIMMUNE.RTM. ORAL formulation (SO).

#FIG. 2 provides the time at which C.sub.max occurred (T.sub.max) for each of formulations shown in FIG. 1, where T.sub.max is provided as relative value compared to the Tmax of SANDIMMUNE.RTM. ORAL formulation (SO).

#FIG. 3 provides the relative area under the blood concentration-time curve (AUC) for each of the formulations shown in FIG. 1, where AUC is provided as a relative value compared to the AUC value for SANDIMMUNE.RTM. ORAL formulation (SO).

#Oral cyclosporin formulations are provided which promote bioavailability and can be formulated as capsules, particularly hard capsules. In the subject formulations, cyclosporin is present in an orally acceptable vehicle comprising at least one alkanol solvent of from 2 to 3 carbon atoms in combination with at least one non-ionic surfactant. The subject formulations may further comprise at least one cosolvent, where cosolvents of interest include fatty acid esters and diols, preferably one or more polyglycols. Each of the components of the subject formulations are pharmaceutically acceptable. In addition to providing for high bioavailability, the subject formulations provide for reproducible cyclosporin absorption from one batch of a particular formulation to the next. The subject formulations find use in immunosuppressive therapy.

#A number of cyclosporins are known in the art to exhibit immunosuppressive activity and may be delivered in the subject oral formulations. Cyclosporins that may be administered in the subject formulations include Cyclosporin A, Cyclosporin B, Cyclosporin C, Cyclosporin D and Cyclosporin G, as well as synthetic analogs thereof. See Merck Index (1989) 2759. The subject oral formulations are particularly suited for the delivery of Cyclosporin A. When delivered in the subject formulations, Cyclosporin A will be present in concentrations ranging from 50 to 150 mg/ml, usually 100 to 150 mg/ml, based on the volume of the vehicle component of the formulation.

#The vehicle component of the subject formulations will include an alkanol solvent component, where the alkanol solvent component will comprise at least one alkanol and usually no more than three different alkanols, more usually no more than two different alkanols, where the alkanols will usually be from 2 to 3 carbon atoms, and from 1 to 2 hydroxy groups, such that there is no more than 1 hydroxy group per 1.5 carbon atoms. Suitable alkanols include ethanol and propylene glycol, preferably absolute ethanol. The total amount of alkanol solvent in the formulation will be at least about 1% (v/v), usually at least about 3% (v/v) and may be as high as 95% (v/v), but will generally range from about 5 to 75% (v/v), usually from about 5 to 60% (v/v), and more usually from about 10 to 60% (v/v) of the formulation. When ethanol is present in the formulation as an alkanol solvent, the amount of ethanol may range from 5 to 25% (v/v), usually from about 5 to 20% (v/v) and more usually from about 10 to 25% (v/v) of the formulation, while when propylene glycol is present as an alkanol solvent, the amount of propylene glycol in the subject formulation may range from about 5 to 90% (v/v), usually from about 5 to 85 % (v/v), more usually from about 10 to 50% (v/v) of the formulation.