Method and formulation for decreasing statin metabolism

Details Method and formulation for decreasing statin metabolism Method and formulation for decreasing statin metabolism

2001-08-22

2003-11-25

Azpuru, Carlos A. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

C424S400000, C424S405000, C424S439000, C424S450000, C424S497000, C424S498000, C424S499000

Reexamination Certificate

active

06652865

ABSTRACT:

CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the priority of French application 01.10094, filed Jul. 27, 2001, the entire disclosure of which is incorporated herein by reference.
FIELD OF THE INVENTION
The invention relates to pharmaceutical methods and oral compositions.
BACKGROUND OF THE INVENTION
It is known from the documents Drug Metab. Disp. (1 995) 23: 279-84 and Transplantation (1992) 53: 596-602 that intestinal metabolism plays an important role in the bioavailability of a certain number of drugs or active principles. Thus, studies have shown that the bioavailability of an active principle can be improved by blocking or reducing the intestinal metabolism [see Clin. Pharmacol. Ther. (1997) 61: 401-9] rather than by acting on the metabolism of the liver. The solution consisting in blocking the intestinal metabolism has a certain risk since it acts directly on the regulatory system. Specifically, cellular transporters have a well-defined role whose regulation depends on the concentration of ligands in the lumen. If, for example, the ligand concentration decreases, the number of transporters increases.
The Applicant has thus sought to reduce the intestinal metabolism which a certain number of molecules undergo.
SUMMARY OF THE INVENTION
The invention relates to pharmaceutical methods and oral compositions comprising an active principle liable to undergo a large first intestinal passage effect. Although the invention concerns all active principles liable to undergo a first intestinal passage effect, this effect is described more particularly in relation to the statins and especially simvastatin, without, however, this being limiting.
The compositions of the invention are in the form of systems that are self-microemulsifying on contact with an aqueous phase. The systems comprise:
a therapeutically effective amount of the active principle;
a lipophilic phase comprising a mixture of glycerol mono-, di- and triesters and of PEG mono- and diesters with at least one fatty acid chosen from the group comprising C
8
-C
18
fatty acids;
a surfactant phase comprising a mixture of glycerol mono-, di- and triesters and of PEG mono- and diesters with caprylic acid (C
8
) and capric acid (C
10
);
a co-surfactant phase comprising at least one ester of an alcohol with at least one fatty acid chosen from the group comprising caprylic esters of propylene glycol, lauric esters of propylene glycol and oleic esters of polyglycerol,
the ratio SA/CoSA being between 0.2 and 6.


REFERENCES:
patent: 6054136 (2000-04-01), Farah et al.
patent: 6248363 (2001-06-01), Patel et al.
patent: 0 670 715 (1997-07-01), None
Vincent F. Mauro “Clinical Pharmacokinetics and Practical Applications of Simvastatin”Clin. Pharmacokinet 24, 195-202 (1993).
Rau et al. “Pharmacokinetics and Drug Disposition—Grapefruit juice—terfenadine single-dose interaction: Magnitude, mechanism, and relevance”Clin. Pharm. &Ther. 61, 401-409 (1997).
Du Souich et al. “Contribution f the Small Intestine to the First-Pass Uptake and Systemic Clearance of Propranolol in Rabbits”Drug Metab. andDisp. 23, 279-284 (1995).

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