Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-07-09
2004-07-06
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C428S403000
Reexamination Certificate
active
06759060
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to new types of particles which can be used alone or as vectors for various compounds. It also relates to a process for the preparation of particulate vectors which makes possible improved control of the active principle charging.
Supramolecular Biovectors or SMBV are particles which are biomimetic of the endogenous vectors of the body and which are capable of encapsulating and of carrying a large number of active principles for, in particular, pharmaceutical, cosmetic or agribusiness use.
A first type of SMBV was described in Application EP 344,040. Their structure is very well suited to the role of vector, in particular as a result of the possibility of modifying their size and their composition according to the molecule or molecules transported and their use.
SMBV are synthesized in three successive steps: synthesis of a central core composed, for example, of crosslinked natural polysaccharide, which can be derived by ionic groups and brought, in particular by ultramilling, to the desired size (between 10 nanometers and a few microns, according to the desired use) establishment of a ring of fatty acids grafted covalently solely at the periphery of the central core, in order to confer a peripheral hydrophobic nature on the latter while retaining its internal hydrophilic nature stabilization of one or of a number of external lipid lamellae, composed in particular of phospholipids or of ceramides, sometimes with the addition of other constituents, for example of constituents of biological membranes.
The active principles, according to their physicochemical characteristics, can be transported either in the external lipid lamellae (in the case of lipophilic or amphiphilic compounds) or within the hydrophilic core (in the case of polar compounds).
Encapsulation of active principles of polar nature can take place, according to the structure of the latter, either before formation of the fatty acid ring or between this step and stabilization of the external lamella.
Despite their suitability for many uses, the synthesis of SMBVs can sometimes cause problems and in particular:
it requires a step which is problematic to control in grafting the fatty acid ring;
this grafting, carried out solely at the periphery of the core, must be carried out homogeneously, which requires in particular a prior drying step, under very specific conditions;
if the active principle is encapsulated before the grafting of the fatty acid ring, some of these molecules, localized, after their encapsulation, at the periphery of the core, can be derived by the fatty acid, leading to modification of the properties of this active principle;
if the active principle is encapsulated after the grafting of the fatty acid ring, the latter can be detrimental to the penetration of the active principle into the hydrophilic core.
BRIEF SUMMARY OF THE INVENTION
The present inventors have shown that, surprisingly, in certain applications, it was possible to scale down the reaction scheme by not grafting the ring of fatty acids and phospholipids to the periphery of the crosslinked hydrophilic core.
The present inventors have shown that the polysaccharide particles thus obtained could be used as is. They are then named PS-type SMBV, by analogy with supramolecular Biovector or PSC (polysaccharidic core).
The present inventors have indeed shown that the polysaccharide particles, even of small size, could be used provided that suitable charging protocols are adopted.
This is why the subject of the present invention is a synthetic particulate vector, characterized in that it comprises:
a non-liquid hydrophilic core.
A further subject of the present invention is a synthetic particulate vector which consists essentially of a non-liquid hydrophilic core.
DETAILED DESCRIPTION OF THE INVENTION
The notion of vector must, in this instance, be understood within the broad meaning, that is to say that it comprises particles having a support role, for example when they are incorporated in a composition, either as such or for the transportation, the presentation and/or the stabilization of active compounds.
A non-liquid hydrophilic core (or matrix) can be a hydrophilic polymer. The hydrophilic matrix can in particular be composed of polysaccharides or oligosaccharides which are naturally or chemically crosslinked. The polysaccharide is preferably chosen from dextran, starch, cellulose and their derivatives.
The hydrophilic core can be obtained by various methods and in particular, if it is a core of polysaccharide nature, by using a branched or linear biodegradable polysaccharide. This polysaccharide can be, for example, starch or one of its derivatives. Crosslinking processes are known to a person skilled in the art and can be carried out by means of bi- or tri-functional agents, such as epichlorohydrin or phosphorus oxychloride.
The properties of the polysaccharide can be modified by grafting the sugars by acidic or basic ionic functional groups which are important for the encapsulation of ionic active principles.
Encapsulation of the hydrophilic active principles can be carried out at this stage of the synthesis. The gel obtained during the synthetic step is then washed and partially dehydrated by means, for example, of centrifugation techniques, then brought into the presence of the active principle and slowly rehydrated. As the gel has the ability to swell with water, the active principle is carried within the polysaccharide network where it can be bound by ionic bonds with the groups grafted within the gel.
The gel obtained, whether it contains or does not contain an encapsulated compound, must be mechanically ground for the purpose of obtaining particles of desired size. The ultramilling methods are known in the state of the art and can in particular involve a high pressure extrusion using a homogenizer.
Another subject of the present invention is a process for the preparation of a particulate vector, comprising:
a) encapsulating a basic ionizable active principle in a crosslinked hydrophilic matrix grafted by acidic ionic ligands, at a pH below the pK
a
of the active principle; and
b) increasing the pH of the medium to a value above the pK
a
of the active principle.
In fact, the adoption of a suitable protocol for the charging of hydrophilic cores makes it possible to control the topology of the charging.
The hydrophilic matrix is preferably composed of polysaccharides or of oligosaccharides, which are naturally or chemically crosslinked.
This process, which can be used with SMBV, is more particularly important with particles in which the external lipid lamellae have been reduced (L-type SMBV) or eliminated (PS-type SMBV) with respect to the method described above. The present inventors have observed that it is difficult to use such SMBV containing reduced lipid lamellae as vectors for the encapsulation of ionic active principles with conventional charging methods.
In fact, if molecules of the active principle are bound with the polysaccharide particle of the core while being maintained at the periphery of the core, this can result in an instability in the particle suspension, it being possible for the particles to aggregate with one another by virtue of interparticulate bonds due to the active principle. This phenomenon is relatively minor for low levels of charging of active principles, whereas it becomes very important with high levels of charging of active principles. Likewise, the size of the particles is extremely important. With particles of large size (for example, greater than 100 manometers), the ratio of the surface area to the internal volume of the particle is very low; for this reason, in comparison with the total amount of active principle encapsulated, the amount of active principle bound at the periphery of the particles is very low, thus limiting the possibilities of interparticulate bonds. In contrast, when the particles are very small in size, this aggregation phenomenon is very noticeable. It should also be noted that this phenomenon is not very marked wi
Betbeder Didier
Candelotto Nadine
De Miguel Igancio
Delrieu Pascal
Ding Li
Biovector Therapeutics S.A.
Burns Doane Swecker & Mathis L.L.P.
Webman Edward J.
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