Nanocapsules based on dendritic polymers

Details Nanocapsules based on dendritic polymers Nanocapsules based on dendritic polymers

2000-02-22

2002-04-30

Dudash, Diana (Department: 1619)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Cosmetic, antiperspirant, dentifrice

C528S271000, C514S788100, C514S772600, C514S975000, C514S963000, C514S725000

Reexamination Certificate

active

06379683

ABSTRACT:

The present invention relates to nanocapsules based on dendritic polymers and to cosmetic and/or dermatological compositions containing them.
The encapsulation or absorption of lipophilic active principles in particles of submicron size has been known for several years and is widely used in particular in cosmetology and dermatology, since these particles, known as nanoparticles, are capable of crossing the superficial layers of the stratum corneum and of penetrating into the upper layers of the live epidermis to release the active principle therein. This penetration into deeper layers broadens the space of action of the active principles and obscures them from rapid removal by simple rubbing.
The term “nanoparticles” primarily encompasses two different systems: “nanospheres” consisting of a porous polymer matrix in which the active principle is absorbed and/or adsorbed, and “nanocapsules” with a structure of core-envelope type, i.e. a structure consisting of a lipid core forming or containing the active principle, this core being encapsulated in a water-insoluble continuous protective envelope. The present invention relates solely to this second vesicular type of nanoparticle, i.e. nanocapsules with a lipid core surrounded by a polymer membrane.
The encapsulation of active principles in capsules of submicron size makes it possible, admittedly, to convey the active molecules more deeply into the skin, but it does not always afford—contrary to what this “protective” structure might lead one to think—sufficient stability of the active principle with respect to the surrounding physicochemical conditions.
The problem of the instability of the active principle arises in particular for substances that are sensitive to oxidation, light, high temperatures and/or acidic or basic pHs. Such a substance which is very commonly used in cosmetics is, for example, retinol (vitamin A
1
), which is sensitive to oxidation, in particular at acidic pH.
One approach for stabilizing retinol consists in adding lipophilic antioxidants and chelating agents to compositions containing it and in adjusting the pH of these compositions to a value of between 5 and 10 (WO 96/31194).
The Applicant has now discovered that encapsulation in nanocapsules based on a specific type of polymer significantly improves the stability of retinol, and does so in particular in the absence of antioxidants and at pH values below 5.
The polymers which allow such a favourable effect to be obtained are known as dendritic polymers. These polymers have a structure of hyperbranch polyester type which will be described in greater detail hereinbelow.
Thus, the encapsulation of retinol in nanocapsules with an envelope formed from dendritic polymers of the type described above gives this active molecule satisfactory stability, i.e. a loss of activity of less than 20% after storage for 1 month at 45° C., whereas, under equivalent conditions, this same molecule encapsulated in other polymers commonly used for nanoencapsulation (for example polycaprolactone or cellulose derivatives) shows a loss of activity at least equal to 30% and possibly being as much as 100%.
One subject of the invention is thus nanocapsules consisting
of a lipid core forming or containing a lipophilic active principle, and
of a water-insoluble continuous envelope comprising at least one dendritic polymer of polyester type containing terminal hydroxyl functions.
A subject of the invention is also cosmetic and/or dermatological compositions containing the said nanocapsules based on dendritic polymers.
Another subject of the invention is a process for preparing nanocapsules based on the above dendritic polymers.
Other subjects will become apparent on reading the description and the examples which follow.
Dendritic polymers or dendrimers (from the Greek dendron=tree) are “arborescent” polymer molecules, i.e. highly branched polymers, which were invented by D. A. Tomalia and his team at the start of the 1990s (Donald A. Tomalia et al.,
Angewandte Chemie, Int. Engl. Ed.
, vol. 29, No. 2, pages 138-175). They are molecular structures constructed around a central unit which is generally multivalent. Linked around this central unit, in concentric layers and according to a fully defined structure, are branched chain-extending units thus giving rise to monodisperse symmetrical macromolecules of well-defined chemical structure and stereochemistry.
The dendritic polymers constituting the envelope of the nanocapsules of the present invention are hyperbranched polymers with the chemical structure of a polyester and which are terminated with hydroxyl groups optionally modified with at least one chain-terminating agent. The structure and preparation of such polymers is described in patent applications WO-A-93/17060 and WO 96/12754.
More specifically, the dendritic polymers used in the compositions of the present invention can be defined as being highly branched macromolecules of polyester type, consisting
of a central unit derived from an initiator compound bearing one or more hydroxyl functions (a),
of chain-extending units derived from a chain-extending molecule bearing a carboxyl function (b) and at least two hydroxyl functions (c), each of the hydroxyl functions (a) of the central molecule being the starting point of a polycondensation reaction (by esterification) which starts with the reaction of the hydroxyl functions (a) of the central molecule with the carboxyl functions (b) of the chain-extending molecules, and then continues by reaction of the carboxyl functions (b) with the hydroxyl functions (c) of the chain-extending molecules.
A “generation X” dendrimer refers to a hyperbranched polymer prepared by X condensation cycles, each cycle consisting in reacting all of the reactive functions of the central unit or of the polymer with one equivalent of a chain-extending molecule.
The initiator compound bearing one or more hydroxyl functions and forming the central unit around which the dendritic structure will be constructed is a monohydroxy, dihydroxy or polyhydroxy compound. It is generally chosen from
(a) a monofunctional alcohol,
(b) an aliphatic, cycloaliphatic or aromatic diol,
(c) a triol,
(d) a tetrol,
(e) a sugar alcohol,
(f) anhydro-ennea-heptitol or dipentaerythritol,
(g) an &agr;-alkylglycoside,
(h) a polyalkoxy polymer obtained by polyalkoxylation of one of the alcohols (a) to (g), with a molar mass of not more than 8000.
As examples of preferred initiator compounds for preparing the dendritic polymers used in the present invention, mention may be made of ditrimethylolpropane, ditrimethylolethane, dipentaerythritol, pentaerythritol, an alkoxylated pentaerythritol, trimethylolethane, trimethylolpropane, an alkoxylated trimethylolpropane, glycerol, neopentyl glycol, dimethylolpropane or 1,3-dioxane-5,5-dimethanol.
These hydroxylated initiator compounds forming the central unit of the future dendrimer are reacted with molecules referred to as chain-extending molecules, which are compounds of monoacidic diol type chosen from
monocarboxylic acids comprising at least two hydroxyl functions, and
monocarboxylic acids comprising at least two hydroxyl functions, one or more of which bear(s) a hydroxyalkyl substituent.
Preferred examples of such compounds are dimethylolpropionic acid, &agr;,&agr;-bis(hydroxymethyl)butyric acid, &agr;,&agr;,&agr;-tris(hydroxymethyl)acetic acid, &agr;, &agr;-bis(hydroxymethyl)valeric acid, &agr;,&agr;-bis(hydroxy)-propionic acid and 3,5-dihydroxybenzoic acid.
According to one particularly preferred embodiment of the present invention, the initiator compound is chosen from trimethylolpropane, pentaerythritol and an ethoxylated pentaerythritol, and the chain-extending molecule is dimethylolpropionic acid.
Some of the terminal hydroxyl functions of the dendritic polymers of polyester type used in the nanocapsules of the present invention can bear substituents derived from at least one chain-terminating agent.
The fraction of these terminal hydroxyl functions bearing a chain-terminating unit is generally between 1 and 90 mol %, preferably be

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