Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-12-21
2003-05-20
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S401000, C424S490000
Reexamination Certificate
active
06565886
ABSTRACT:
The present invention relates to nanocapsules based on polyesters of poly(alkylene adipate) type, to a process for their preparation and to cosmetic or dermatological compositions containing them.
The encapsulation or absorption of lipophilic active principles in particles of submicron dimensions has been known for several years and is widely used in particular in the fields of cosmetology and dermatology. Specifically, these particles, known as nano-particles, are capable of crossing the superficial layers of the stratum corneum and of penetrating into the upper layers of the living epidermis to release the active principle therein. This penetration into deeper layers broadens the space of action of the active principles and shelters them from rapid elimination by simple rubbing.
The term “nanoparticles” mainly 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 centre forming or containing the active principle, this centre being encapsulated in a water-insoluble continuous protective envelope. The present invention relates exclusively to this second vesicular type of nanoparticles, 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 transport the active molecules more deeply into the skin, but—contrary to what this “protective” structure might lead one to think—it does not always provide the active principle with sufficient stability with respect to the surrounding physicochemical conditions.
The problem of the instability of the active principle arises in particular for substances which 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) which is sensitive to oxidation in particular at acidic pH.
One approach for stabilizing retinol consists in adding lipophilic antioxidants and chelating agents to the 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 discovered that encapsulation in nanocapsules based on a specific type of polymer makes it possible to improve the stability of retinol spectacularly, in particular in the absence of antioxidants.
The polymers which make it possible to obtain such a favourable effect are polyesters of poly(alkylene adipate) type described in greater detail below.
Thus, the encapsulation of retinol in nanocapsules with an envelope formed from polyesters of poly(alkylene adipate) type gives this active molecule satisfactory stability, i.e. a loss of activity of only 5 to 10% after storage for 2 months at 45° C., whereas, under equivalent conditions, this same molecule encapsulated in other polymers commonly used for nanoencapsulation (for example polycaprolactone or cellulose derivatives) has a loss of activity of greater than 20%.
One subject of the invention is thus nanocapsules consisting
of a lipid centre forming or containing a lipophilic active principle, and
of a water-insoluble continuous polymeric envelope comprising at least one polyester of poly(alkylene adipate) type.
Another subject of the invention is cosmetic and/or dermatological compositions containing the said nanocapsules based on poly(alkylene adipate).
Another subject of the invention is a process for preparing the above nanocapsules based on poly(alkylene adipate).
Other subjects will become apparent on reading the description and the examples which follow.
The polyesters which can be used to form the envelope for the nanocapsules are polymers obtained by polycondensation of an aliphatic dicarboxylic acid, namely adipic acid (hexane-1,6-dioic acid), and of one or more diols and, optionally, of a small proportion of triols.
The term poly(alkylene adipate) used in the present patent application to denote the polyesters forming the envelope of the nanocapsules encompasses both homopolymers of adipic acid and of an alkanediol and copolymers of linear or branched poly(ester ether) type, obtained from adipic acid and from one or more alkanediols and/or ether-diols and/or triols.
The alkanediols used for the preparation of the said poly(alkylene adipates) are C
2
-C
6
alkanediols with a linear or branched chain, chosen from ethylene glycol, propylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol and neopentyl glycol.
The ether-diols are di, tri- or tetra(C
2
-C
4
alkylene) glycols, such as diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, tripropylene glycol, tetrapropylene glycol or dibutylene glycol, tributylene glycol or tetrabutylene glycol.
As indicated above, the polyesters of poly(alkylene adipate) type used for the preparation of the nanocapsules of the invention can also contain a limited number of branching units derived from triols.
The triols used are generally chosen from glycerol, trimethylolethane, and trimethylolpropane.
The fraction of the branching units derived from the above triols generally does not exceed 5 mol % relative to the total number of units derived from diols and triols.
According to one preferred embodiment of the present invention, the envelope for the nanocapsules is formed from a poly(ethylene adipate) or from a poly(butylene adipate).
The poly(alkylene adipates) used in the present invention have a weight-average molar mass (measured by gel permeation chromatography) of between 2000 and 50,000, preferably between 5000 and 15,000.
This molar mass range is limited on the one hand, for low masses, by an excessive content of residual oligomers and monomers, and, for high masses, by an unacceptable production cost.
The poly(alkylene adipates) used in the present invention are known and can be prepared according to known processes.
A whole range of products of different chemical composition and of different mass is sold under the name Fomrez® by the company Witco. The company Scientific Polymer Products sells, under the name Poly(ethylene)adipat®, a poly(ethylene adipate) with a weight-average molar mass (determined by GPC) of about 10,000.
The polyesters of poly(alkylene adipate) type as described above are used to prepare nanocapsules consisting of a lipid centre forming or containing a lipophilic active principle surrounded by an envelope formed from these polymers.
The process for preparing nanocapsules which is preferably used by the Applicant is the one described in EP-A-0,274,961 and comprises the steps consisting
in dissolving the polymer, the lipid phase forming or containing the active principle, and optionally a surfactant which acts as coating agent, in a suitable organic solvent, i.e. a solvent which is miscible with water, non-toxic and more volatile than water (generally acetone and/or a lower alcohol),
in preparing a solution of a suitable surfactant in water (which is a non-solvent for the polymer and the lipid phase),
in adding the organic phase to the aqueous phase with moderate stirring thereof, which results in the spontaneous formation of a nanocapsule emulsion,
and then in evaporating the organic phase and, possibly, some of the aqueous phase, in order to obtain a concentrated suspension of nanocapsules in an aqueous phase.
This preparation process generally involves heating the organic phase and/or the aqueous phase to temperatures of between 35 and 70° C. The poly(alkylene adipates) used in the present invention make it possible to carry out this process at room temperature, which constitutes an important advantage in particular for heat-sensitive active substances such as retinol.
The surfactant dissolved in the aqueous phase serves mainly to control the size of the nanocapsules. The reason for this is that it ensures the stability of the nanocapsules in the emulsion resulting from the addition of the acetone phase to the aqueous phase, and prevents
Biatry Bruno
Richart Pascal
Simonnet Jean-Thierry
Dees Jose′ G.
George Konata M
L'Oreal
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