Antithrombotic formulation, process for its manufacturing, and u

Details Antithrombotic formulation, process for its manufacturing, and u Antithrombotic formulation, process for its manufacturing, and u

1995-12-18

1998-08-18

MacMillan, Keith

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

A61K 31505

Patent

active

057958963

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to a new pharmaceutical formulation comprising the thrombin inhibitor HOOC--CH.sub.2 --(R)-Cgl-Aze-Pab in combination with one or more absorption enhancing agents, a process for the preparation of such a pharmaceutical formulation, and the use of such a formulation in the treatment of thromboembolism as well as a method of treating a patient in need of such a treatment by using said formulation.


BACKGROUND

Blood coagulation is the key process involved in both haemostasis (i.e. prevention of blood loss from a damaged vessel) and thrombosis (i.e. the pathological occlusion of a blood vessel by a blood clot). Coagulation is the result of a complex series of enzymatic reactions; one of the final steps is conversion of the proenzyme prothrombin to the active enzyme thrombin.
Thrombin plays a central role in coagulation. It activates platelets, it converts fibrinogen into fibrin monomers, which polymerize spontaneously into filaments, and it activates factor XIII, which in turn crosslinks the polymer to insoluble fibrin. Thrombin further activates factor V and factor VIII in a positive feedback reaction. Inhibitors of thrombin are therefore expected to be effective anticoagulants by inhibition of platelet activation, fibrin formation and fibrin stabilization. By inhibiting the positive feedback mechanism such inhibitors are expected to exert inhibition early in the chain of events leading to coagulation and thrombosis.
Peptidic or peptide like thrombin inhibitors, like many other peptide-like substances, are prone to limited or variable absorption when administered. This is due to the influence of different barriers of metabolic and physical character, such as enzymatic degradation, tendencies toward complex formation with components from the formulation or the biological environment, limitations in transport possibilities etc. One object of the present pharmaceutical formulation is to facilitate for the active agent to overcome such barriers, and to obtain an enhanced and reproducible absorption of the active agent. Formulation components that have such influence and thus can help the active agent are called absorption enhancers.


Prior Art

Concerning the use of absorption enhancers in pharmaceutical formulations, several reports and reviews in the literature exist. Enhancing properties have been reported of different types of substances, such as surface active agents and lipids, chelators, and polymers. Comprehensive reviews have been presented by E J van Hoogdalem et al., Pharmac Theor vol 44, 407-443 (1989), by S Muranishi, Crit Rev Ther Drug Carrier Syst vol 7, 1-33 (1990), by E S Swenson and W J Curatolo, Adv Drug Deliv Rev vol 8, 39-92 (1992), and in Drug Absorption Enhancement (Ed.: A B G de Boer), Harwood Academic Publishers 1994.


DISCLOSURE OF THE INVENTION

It has been found that the absorption of the therapeutically active thrombin inhibitor HOOC--CH.sub.2 --(R)Cgl-Aze-Pab can be modified by incorporating enhancing agents in the pharmaceutical formulations containing said therapeutically active compound.
Therefore, an object of the present invention is to provide novel pharmaceutical formulations comprising the thrombin inhibitor HOOC--CH.sub.2 --(R)-Cgl-Aze-Pab in combination with one or more absorption enhancing agents and optionally a pharmaceutically acceptable carrier, and a process for the preparation of such pharmaceutical formulations.
Means of obtaining improved formulations of this therapeutically active drug are based on the use of absorption enhancing agents, such as, but not limited to, surface active agents, lipids, other drugs and polymers to obtain positive effects which result in an enhanced and/or less variable absorption of the therapeutically active agent when said agent is given by different administration routes, such as oral, rectal, buccal, nasal, pulmonary, inhalation route etc., and combinations of such agents to obtain even positive synergistic effects which result in even higher enhanced absorption.
The absorptio

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