Particulate vector and pharmaceutical composition containing it

Details Particulate vector and pharmaceutical composition containing it Particulate vector and pharmaceutical composition containing it

1996-01-31

1999-04-06

Webman, Edward J.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

428403, 427 214, A61K 916, A61K 919

Patent

active

058914757

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a new type of particulate vector for the transport and presentation of molecules of active ingredients which are at least partially hydrophobic and which interact with specific cell receptors. It also relates to a process for enhancing and controlling the activity of such molecules, in particular of molecules of lymphokines.
The cytokines (also called lymphokines) constitute a group of proteins which play an important role in the regulation and the function of the immune system. They have pleiotropic actions and act by specific interaction with cell receptors with a very high affinity. Some are used or proposed as therapeutic agents (e.g. interferons, interleukin-2 . . . ). One of them, interleukin-2 (IL-2) is particularly representative of this family.
IL-2 is synthesized predominantly by the helper T lymphocytes (Th1) in response to a stimulation by the antigen presented by appropriate cells. It is involved in the development of the specific and nonspecific immune responses: it interacts with various cells in order to activate them (T and natural killer--NK--lymphocytes), in order to induce their proliferation and their differentiation (T, NK and B lymphocytes). IL-2 has antitumor properties: it can induce regression of various solid tumors, of melanomas, leukemias or of lymphomas and the like. IL-2 is also of interest in vaccinology: it enhances especially the protective power of certain viral (herpes, rabies . . . ) and bacterial (Haemophilus pleuripneumoniae) vaccines.
IL-1 has been proposed for protecting the myeloid cells against the cytotoxic effect of chemotherapy.
Hematopoietic growth factors of the G-CSF and GM-CSF type can be used in the treatment of certain types of leukopenia especially after chemotherapy.
The administration of .gamma.-interferon appears to limit the phenomena of allergy by blocking the production of IL-4.
Nevertheless, these are molecules which are capable of taking part in a cascade of biological reactions, sometimes synergistically, and which are capable of bringing about disturbing side effects (fever, erythema, edema).
In addition their purification is difficult and they are often produced by genetic engineering and are therefore expensive.
It would therefore be desirable to be able to have a vector system which makes it possible to decrease the administered doses, through an increase in the observed activity for the same concentration of active molecule and through an extension of the duration of action over time.
Accordingly, the subject of the present invention is a particulate vector, characterized in that it comprises, from the inside to the outside, covalent bonds.
The core of this particulate vector has, preferably, a size of between 10 nm and 5 .mu.m.
The transport systems described up until now have a structure mimicking that of the lipoproteins, in particular at the level of the external surface. This is the case especially for liposomes which consist of a lipid double layer surrounding an aqueous vacuole. This is also the case for the supramolecular biovectors (SMBV) described in patent EP 344 040, which contain an external layer of amphiphilic compounds.
Nevertheless, this type of structure is perhaps not capable of being used for certain classes of active ingredients, with which there is a risk of undesirable interactions occurring, leading to the disorganization of the vector and to the loss of its properties. In particular, for IL-2, no satisfactory transport system exists up until now.
One object of the present invention is therefore to provide an efficient vector having a simpler structure. Surprisingly, it was found that particles comprising only a hydrophilic core, preferably consisting of a matrix of naturally or chemically cross-linked polysaccharides or oligosaccharides, and of an external lipid layer, make it possible to bind active ingredients having a biological activity and to considerably increase the efficacy thereof.
The core may be nonionic or ionic.
An ionic core is obtained by grafting, onto the hydrophilic

REFERENCES:
patent: 5151264 (1992-09-01), Samain et al.

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