Composition with sustained release of active principle,...

Details Composition with sustained release of active principle,... Composition with sustained release of active principle,...

2001-02-02

2001-10-30

Page, Thorman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S484000, C424S487000, C424S488000

Reexamination Certificate

active

06309665

ABSTRACT:

The invention relates to a composition with sustained release of active principle which can be administered orally in particular, for pharmaceutical or cosmetic use, which is capable of forming a microemulsion with an external hydrophilic phase, for example physiological fluid or water, while at the same time gradually releasing the active agent it contains in situ. The invention also relates to the process for manufacturing the said composition.
As is known, a microemulsion is a homogeneous, fluid, stable solution consisting of four major constituents, a hydrophilic phase, a lipophilic phase, at least one surfactant (SA) and at least one co-surfactant, respectively. Microemulsions are distinguished from emulsions and micellar solutions in particular by the size of the droplets of which they are formed. Specifically, the droplet size of a microemulsion is between 10 and 200 nanometres (nm) whereas it is less than 10 nm for a micellar solution and greater than 200 nm for an emulsion. Moreover, in contrast with emulsions, which are unstable, microemulsions, which necessarily comprise a co-surfactant, are stable. Furthermore, a microemulsion is characterized by its more or less pronounced transparency due-to the proportion of reflected light transmitted by a light beam, the intensity of the light beam which is passed through being less than that of the incident beam. Since the reflected light is richer in blue and violet radiation, finely dispersed microemulsions have a bluish appearance. This is the so-called Tyndall effect described in particular in the book “Emulsions, micro-émulsions, emulsions multiples [Emulsions, microemulsions and multiple emulsions]” by Jean Poré.
In document EP-A-0 670 715, the Applicant disclosed a composition formed of a vector system of self-microemulsifiable active agent known by the expression SMEDDS®, a trademark registered by the Applicant, meaning Self Micro Emulsifying Drug Delivery System. These systems are disclosed at length in the abovementioned document and essentially comprise:
an active agent,
a lipophilic phase consisting of a mixture of mono-, di- and triglycerides and of C
8
-C
18
fatty acids and of polyethylene glycol monoesters and diesters with a hydrophilic/lipophilic balance (HLB) of less than 16;
a glyceride-based surfactant (SA) with an HLB of less than 16, chosen from the group comprising saturated C
8
-C
10
polyglycosylated glycerides and oleic esters of polyglycerol;
a co-surfactant (CoSA) chosen from the group comprising lauric esters of propylene glycol, oleic esters of polyglycerol, ethyl diglycol and polyethylene glycol;
the SA-CoSA ratio being between 0.5 and 6.
Certain products sold by the Applicant, consisting of saturated and/or unsaturated fatty acids and of esters of these fatty acids, may be used as lipophilic phase, surfactant and co-surfactant, such as, for example, the combination of Gelucire 44/14, Labrafac CM10 and Lauroglycol, respectively, disclosed in Examples 1 and 2 of the abovementioned document.
The SMEDDS®s may be in solid or liquid form at room temperature, depending on the actual nature of the fatty substances of which they are composed. Thus, if at least one of the fatty substances constituting the SMEDDS® has a melting point which is greater than room temperature (about 25° C.), then the SMEDDS® will be semi-solid at room temperature. On the other hand, if at least one fatty substance constituting the SMEDDS® has a melting point of less than about 25° C., then the SMEDDS® is liquid at room temperature.
Consequently, the SMEDDS®s may be incorporated into gel capsules in liquid form, optionally while warm, and then, depending on the nature of their constituents, remain liquid or become semi-solid at room temperature.
Due to the formation of the microemulsion in situ, SMEDDS®s make it possible to dissolve the active principle and consequently to increase the bioavailability of the microemulsified active agent(s) they convey. However, the formation of the microemulsion gives the composition properties of immediate release of microemulsified active agent.
In other words, the problem which the invention proposes to solve is that of providing a composition of the SMEDDS® type which is capable of gradually releasing the active agent(s) it conveys, and of doing so whatever the consistency, solid or liquid, of the SMEDDS® at room temperature.
To solve this problem, the invention proposes a composition with sustained release of the active principle, for pharmaceutical or cosmetic use, which is intended to be ingested, comprising a system which is self-microemulsifying on contact with a hydrophilic phase provided, after ingestion, by the physiological fluid, the said self-microemulsifying system comprising:
at least one active agent,
a lipophilic phase consisting of a mixture of mono-, di- and triglycerides and of C
8
-C
18
fatty acids and of polyethylene glycol monoesters and diesters with a hydrophilic/lipophilic balance (HLB) of less than 16;
a glyceride-based surfactant (SA) with an HLB of less than 16, chosen from the group comprising saturated C
8
-C
10
polyglycosylated glycerides and oleic esters of polyglycerol;
a co-surfactant (CoSA) chosen from the group comprising fatty acid esters of propylene glycol, oleic esters of polyglycerol, ethyldiglycol and polyethylene glycol;
the SA-CoSA ratio being between 0.5 and 6.
The composition of the invention is characterized in that it also comprises an inert polymer matrix which is not ionizable at physiological pH, dispersed in the self-microemulsifying system before ingestion, the said polymer matrix being capable, after ingestion, of forming, in contact with physiological fluid, a gelled polymer matrix making it possible to release the thus microemulsified active agent in a continuous and sustained manner by diffusion.
In the description hereinbelow and in the claims, the expression “microemulsified active agent” denotes the active agent dissolved in the microemulsion, i.e. in its hydrophobic zone.
Similarly, the expression “physiological fluid” denotes the physiological medium in vivo, as is found after ingestion of the composition and the pH of which will vary as a function of the state of the gastrointestinal tract.
However, at the experimental stage, i.e. without ingestion of the composition, the physiological fluid is replaced with water or a physiological medium reconstituted in vitro. In this case, the microemulsion will be formed on simple contact with the aqueous phase.
Hereinbelow in the description and in the claims, the expression “polyglycosylated glycerides” denotes a mixture of mono-, di- and triglycerides and of polyethylene glycol (PEG) mono- and diesters with a molecular weight preferably of between 200 and 600, optionally of glycerol and of free PEG, the HLB value of which is controlled by the chain length of the PEG and the melting point of which is controlled by the chain length of the fatty acids, of the PEG and of the degrees of saturation of the fatty chains, and thus of the starting oil.
Similarly, the expression “C
8
to C
18
fatty acids”, also written C
8
-C
18
fatty acids, denotes mixtures in significant and variable proportions of caprylic (C
8
) acid, capric (C
10
) acid, lauric (C
12
) acid, myristic (C
14
) acid, palmitic (C
16
) acid and stearic (C
18
) acid, when these acids are saturated, and the corresponding C
8
-C
18
unsaturated acids.
It is recalled that the proportions of these fatty acids may vary as a function of the starting oils.
In one preferred embodiment of the invention, the co-surfactant is chosen from the group comprising lauric esters of propylene glycol, capric esters of propylene glycol and palmitic esters of propylene glycol.
In other words, the invention consists in incorporating an inert polymer matrix into a self-microemulsifying system. The said self-microemulsifying system thus forms a microemulsion after ingestion, on contact with physiological fluid, thus making it possible, by diffusion through the matrix which has thus become gelled on contact with the physiological fluid, to gr

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