Tacrolimus For Improved Treatment Of Transplant Patients

Abstract

An extended release oral dosage form comprising as active substance tacrolimus or a pharmaceutically active analogue thereof for a once daily immunosuppressive treatment of a patient in need thereof, preferable a kidney or liver transplant patient. The dosage form releases the active substance over an extended period of time. It also provides improved pharmacokinetic parameters due to an extended and constant in vivo release including substantial decreased peak concentrations, despite increased bioavailability, substantial extended times for maximal concentration, and higher minimal concentrations when compared with conventional immediate release dosage forms and a recent modified release tacrolimus dosage form.

Description

RELATED U.S. APPLICATION[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 079,015, filed Jul. 8, 2008, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to an extended release oral dosage form comprising as active substance tacrolimus or a pharmaceutically active analogue thereof for use in a once daily immunosuppressive treatment of a patient in need thereof which dosage form releases the active substance over an very extended period of time and which in vivo provides a high bioavailability and an improved pharmacokinetic profile compared to conventional dosage forms.BACKGROUND OF THE INVENTION[0003]Tacrolimus, also known as FK-506 or FR-900506, is the active ingredient of Prograf®, Protopic®, and Advagraf® approved by the European Agency for the Evaluation of Medicinal Products (EMEA) at 23 Apr. 2007. During development of Advagraf® the product has been known as MR4. Details of Advagra...

AI Technical Summary

Benefits of technology

The extended release formulation achieves significantly increased bioavailability and improved pharmacokinetic profiles, reducing variability and side effects, allowing for a once-daily dosing regimen with stable blood concentrations, enhancing treatment efficacy and safety for transplant patients.

Problems solved by technology

It is generally accepted that extending the release too much may seriously affect the bioavailability even with substances expected to have a good permeation in the colon.

Accordingly, the control and timing of the in vivo release of the extended release dosage form in order to obtain a predictable release under the various physical conditions present along the GI tract is a challenge, especially bearing in mind that immune suppressive treatment in transplant patients requires blood concentrations within very narrow limits to balance efficacy (lack of rejection) and side effects (infections, nephrotoxicity, metabolic and cardiovascular disease, etc).

Further factors decreasing the risk of clinical success with a once daily formulation in organ transplant includes high prevalence of gastrointestinal complications having impact on the gastrointestinal parameters including transit times, pH, bacterial composition and other functions of the GI system.

These complications include nausea, vomiting, and very frequently diarrhea.

However, exceptions may apply if for instance one formulation has a pH dependent release and the other not, and the actual pH values for testing are not chosen to detect such difference.

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