EP2413918A1

EP2413918A1 - Solid lipid nanoparticles encapsulating minoxidil, and aqueous suspension containing same

Info

Publication number: EP2413918A1
Application number: EP10715993A
Authority: EP
Inventors: Karine Padois; Fabrice Pirot; Françoise FALSON
Original assignee: Universite Claude Bernard Lyon 1 UCBL
Current assignee: Universite Claude Bernard Lyon 1 UCBL
Priority date: 2009-03-31
Filing date: 2010-03-29
Publication date: 2012-02-08
Also published as: FR2943545B1; WO2010112749A1; FR2943545A1

Abstract

The present invention relates to a suspension of solid lipid nanoparticles in an aqueous phase wherein: the solid lipid nanoparticles encapsulate minoxidil in a lipid matrix, and further include at least one amphiphilic compound A1 selected from phospholipids, and in particular from phosphatidylcholines and lecithins, propylene glycol, one or more surfactants and optionally ethanol, the aqueous phase containing water, propylene glycol and optionally ethanol. The invention also relates to the corresponding nanoparticles, to a method for producing same, as well as to cosmetic and pharmaceutical compositions containing same.

Description

SOLID LIPID NANOPARTICLES ENCAPSULATING MINOXIDIL AND AQUEOUS SUSPENSION CONTAINING SAME

The invention relates to compositions comprising minoxidil, useful in particular for combating hair loss. In particular, the invention relates to novel compositions in the form of an aqueous suspension of solid lipid nanoparticles containing minoxidil, their method of preparation, and their use for combating hair loss and / or promoting their regrowth. .

Minoxidil or 6- (1-piperidinyl) -2,4-diamine-3-oxide pyrimidine (CAS: 38304-91-5) of formula:

is especially used, in the form of composition for topical application on the scalp, in order to stop hair loss and allow their regrowth. Several topical compositions of minoxidil have already been marketed.

Minoxidil is known for its very low solubility in an aqueous medium. In some of the compositions so far developed, minoxidil is associated with a solvent or mixture of low polar solvents, such as propylene glycol, to improve its solvation and thus its penetration to the hair bulb.

However, these solvents impart a bold and unattractive character to the hair, making such compositions difficult to use because their use on the scalp is very unpleasant. In addition, propylene glycol is known for a sensitizing effect on the mucous membranes. It has therefore been envisaged to implement hydro-alcoholic solutions to limit the use of propylene glycol. Nevertheless, the use of hydroalcoholic solutions containing ethanol is often responsible skin intolerances, manifested in particular in various forms such as irritations or acne and increases, thus, the number of failures to treatment.

Recently, solutions have been proposed in which minoxidil is encapsulated in molecular form in liposomes or niosomes, i.e., uncharged surfactant vesicles (Journal of Drug Targeting, 23007, vol.15, issue, 2, p 101-108). Nevertheless, such techniques do not make it possible to achieve satisfactory levels of encapsulation with minoxidil and, moreover, the low stability of the compositions obtained is problematic.

The publication of A. C. Silva et al. in Pharmazie, 2009, 64, 3, 177-182 describes, in turn, an aqueous suspension of nanostructured lipid carriers (named NLC) and a hydrogel obtained from such a suspension comprising a mixture of stearic acid and oleic acid, poloxamer 188, 0.3% by weight of minoxidil and carbopol 940 or perfluorocarbon (PFC). This type of formulation, because of the presence of stearic acid and oleic acid are irritating when applied cutaneously. In addition, these NLCs are formed, at room temperature, of a lipid matrix composed of solid and liquid lipids in variable proportion. Such formulations do not make it possible to encapsulate minoxidil levels, in particular of the order of 3 to 4%.

The present invention is concerned with the development of minoxidil compositions in which the minoxidil will be dispersed within solid lipid nanoparticles conventionally called SLN. The nanoparticles belong to a family of colloidal vectors that can be used, for example, for the administration of active principles, such as therapeutic molecules in humans or animals. Such colloidal vectors preserve these active principles and can allow their controlled and / or prolonged release at their site of action. The patent application WO 99/39700 (D2) describes pharmaceutical compositions in the form of solid nanoparticles comprising a composite material which consists of at least one lipid substance and at least one amphiphilic substance and a pharmaceutical active principle water soluble, hyposoluble or poorly soluble. Minoxidil is cited among a large number of active ingredients, but none of the examples relate to formulations based on minoxidil. In addition, the examples given in this document with other active ingredients contain stearic acid and therefore pose the same types of problems as those mentioned above for the publication of AC Silva et al.

Also, one of the objectives of the invention is to provide compositions based on solid lipid nanoparticles containing minoxidil, which are stable and easy to prepare, and at a lower cost. Another object of the invention is to provide compositions based on minoxidil which are suitable for topical application. Also, the invention proposes to provide compositions leading to a satisfactory penetration in the skin of minoxidil, particularly with respect to existing commercial compositions based on ethanol. The invention is also directed to compositions which may make it possible to modulate the release of minoxidil.

Another object of the invention is to provide compositions which are well tolerated for topical application and which in particular do not require the presence of alcohol such as ethanol or at least not more than 2% by weight of ethanol.

In this context, the present invention relates to a suspension of solid lipid nanoparticles in an aqueous phase in which: the solid lipid nanoparticles encapsulate minoxidil in a lipid matrix, and furthermore comprise at least one amphiphilic compound A1 chosen from phospholipids, and in particular from phosphatidylcholines and lecithins, propylene glycol, one or more surfactants and optionally ethanol, the aqueous phase contains water, propylene glycol and optionally ethanol.

According to another of its aspects, the invention relates to solid lipid nanoparticles encapsulating minoxidil in a matrix lipid, and further comprising at least one amphiphilic compound Al selected from phospholipids, and in particular from phosphatidylcholines and lecithins, propylene glycol, one or more surfactants and optionally ethanol. The invention also relates to cosmetic or pharmaceutical compositions comprising such suspensions or such solid lipid nanoparticles.

The invention also relates to a process for preparing a suspension according to the invention comprising the following steps: - obtaining a mixture of the amphiphilic compound A1 chosen from phospholipids, and in particular from phosphatidylcholines and lecithins, with propylene glycol, the surfactant (s), the minoxidil and the lipid matrix maintained at a temperature above its melting temperature, and, optionally, ethanol, emulsification of the mixture obtained in water, solidification of the lipid nanoparticles obtained, by cooling.

The invention also relates to a method for preparing solid nanoparticles according to the invention comprising, in addition to the above steps, a lyophilization step.

Some definitions of terms used in the context of the description of the invention are given below.

"Solid" lipid nanoparticles means nanoparticles which are in the solid state, at least at a temperature close to ambient temperature, especially at a temperature in the range of 10 to 30 ^° C. Such nanoparticles are completely solid in this temperature range: they do not contain liquid lipids like NLCs. The HLB (hydrophilic lipophilic balance) of the surfactant or surfactant mixture will be determined by the Griffin method. (Griffin WC: Classification of Surface Active Agents by ¹ HLB, Journal of the Society of Cosmβtic Chemists 1 (1949): 311. Griffin WC: Calculation of HLB Values of Non-Ionic Surfactants, Journal of the Society of Chemical Chemists (1954): 259).

The diameter of the solid lipid nanoparticles, which corresponds to the average diameter weighted by the diffused light intensity of the nanoparticles, will be determined, directly on the suspensions after dilution in water, by photon correlation spectroscopy, for example with the aid of Zetamaster® from Malvern. Nanoparticles means particles of substantially spherical shape, with a diameter of less than or equal to 500 nm. In particular, the solid lipid nanoparticles according to the invention have a diameter in the range of 100 to 500 nm, preferably in the range of 150 to 300 nm.

The polydispersity index is the width of the distribution, that is the equivalent of the variance on a lognormal distribution, calculated directly by the Zetamaster® device. This parameter indicates the distribution width of a suspension of nanoparticles. If the value is between 0.000 and 0.003 the sample is said to be monodisperse; from 0.03 to 0.08 the sample is said to be almost monodisperse; from 0.08 to 0.50 the sample is said to be polydisperse; and greater than 0.5 the sample is said to be very polydisperse. The supers according to the invention preferably has a polydispersity index of 0.00 to 0.50.

The suspension according to the invention comprises various constituents: a dispersed phase which corresponds to the solid lipid nanoparticles in which the minoxidil is found, solubilized in the lipids thanks to the amphiphilic compound Al, to propylene glycol, to the (x) surfactant (s) and to ethanol optionally present, an aqueous phase comprising water, propylene glycol, and optionally ethanol. Such a suspension advantageously has a pH close to neutrality and close to the pH of the skin, that is to say between 5 and 7. The percentages given in the rest of the description are percentages by weight. When the percentages relate to the suspension, the percentages are given with respect to the total mass of the aqueous suspension. On the other hand, when the percentages relate to the solid lipid nanoparticles, the percentages are given with respect to the total mass of solid lipid nanoparticles alone.

According to an essential characteristic of the invention, the solid lipid nanoparticles comprise an amphiphilic compound Al which will make it possible to solubilize the minoxidil in the lipid matrix. This amphiphilic compound Al is chosen from phospholipids, and in particular from phosphatidylcholines and lecithins. Lecithins correspond to phospholipids extracted from the living, such as soy lecithin, comprising a significant proportion of phosphatidylcholines. According to a particular embodiment, the amphiphilic compound Al comprises soy lecithin or consists exclusively of soy lecithin. The soy lecithin used is preferably predominantly phosphatidylcholines (i.e., phosphatidylcholines account for more than 50% by weight of the soy lecithin used). It will be possible, for example, to use soy lecithin, in particular marketed under the trade name Phospholipon®. The aqueous suspension may, for example, comprise from 1 to 10%, preferably from 1.5 to 5% by weight of amphiphilic compound Al. Similarly, the solid lipid nanoparticles may, for example, comprise from 1 to 20%, preferably from 5 to 15% by weight of amphiphilic compound Al. The lipid matrix will be chosen to be compatible with an administration in humans or animals and will, in particular, be chosen from non-toxic lipids. According to one embodiment of the invention, the lipid matrix comprises at least one lipid L1 chosen from mono-, di- and triglycerides. According to another embodiment that can be combined with the above, the lipid matrix does not include stearic acid. The lipid matrix may consist exclusively of mono-, di- and triglycerides. For example, the lipid L1 may be a mixture of triglycerides Cn-Cis- Suppocire® is an example of a Ci ₂ -Ci ₈ triglyceride. The suspension may, for example, comprise from 5 to 30%, preferably from 5 to 15%, by weight of lipid L1. Similarly, the solid lipid nanoparticles may, for example, comprise from 35 to 80%, preferably from 35 to 55% by weight of lipid L1.

The suspension according to the invention comprises propylene glycol shared between the solid lipid nanoparticles and the aqueous phase. In fact, during the manufacturing process, which will be detailed in the following description, the propylene glycol is in the lipid mixture which is in liquid form. At the end of the process, when there is solidification of the nanoparticles, it is shared between the aqueous phase and the solid lipid nanoparticles, according to its partition coefficient μP = -1.34. According to an advantageous characteristic, the suspension comprises from 1 to 10%, preferably from 1 to 5% by weight of propylene glycol. Similarly, the solid lipid nanoparticles may, for example, comprise from 0.1 to 2%, preferably from 0.1 to 0.75% by weight of propylene glycol.

With respect to compositions of the lotions type which would use alcohol / polyalcohol combinations, such as ethanol / polyethylene glycol, the suspensions or nanoparticles according to the invention, when they are not used in the form of an aqueous suspension, from the presence of all the selected constituents, allow, in preferred embodiments, to use a much smaller amount of propylene glycol, which allows in particular to have a much more pleasant composition to use in the case of a direct application on the hair. The aqueous phase in which the lipid nanoparticles are dispersed, when in the form of an aqueous suspension, comprises water, in addition to the propylene glycol shared between the aqueous phase and the nanoparticles. The composition comprises, for example, from 50 to 90%, preferably from 65 to 75% by weight of water. Advantageously, the aqueous phase of the suspension consists essentially of water and propylene glycol. By way of example, a suspension according to the invention may contain a small amount of ethanol corresponding to 0.1 to 2% by weight. mass of the composition and preferably from 0.1 to 0.5%. Ethanol is shared between the aqueous phase and the solid lipid nanoparticles. Also, the solid lipid nanoparticles may, for example, comprise from 0.1 to 1.5%, preferably from 0.1 to 0.75% by weight of ethanol.

The solid lipid nanoparticles according to the invention also contain one or more surfactants which make it possible to emulsify the lipid part in water, during their preparation in the form of a suspension and also ensure the stability of the suspension obtained. once the lipid matrix has solidified. By way of example, the surfactant (s) is (are) chosen from esters of fatty and sorbitan fatty acids and esters of polyoxyethylenated fatty acids and of sorbitan. By way of example of such surfactants, mention may be made of Montanox®, Montane®, Tween® and Span®. Advantageously, the surfactant (s) has (s) an HLB in the range of 7.0 to 11.0, preferably 8.5 to 9.5. Such HLB values make it possible to improve the stability of the aqueous suspension. A suspension according to the invention will comprise, for example, from 1 to 15%, preferably from 8 to 12% by weight of surfactant (s). Similarly, the solid lipid nanoparticles may, for example, comprise from 5 to 45%, preferably from 10 to 30% by weight of surfactant (s).

Finally, a suspension according to the invention contains, for example, from 0.1 to 10% and preferably from 3 to 7% by weight of minoxidil, which makes it compatible with its use in pharmaceutical compositions according to the invention. Solid lipid nanoparticles thus comprise from 1 to 30%, preferably from 15 to 29% by weight of minoxidil. Solid lipid nanoparticles may also contain one or more preservatives conventionally used for this type of application.

Furthermore, it has been found that at low temperature (<13 ^° C.) the suspensions according to the invention have a tendency to set in bulk. Also, the suspensions according to the invention advantageously contain a cryoprotective agent and, in particular NaCl, which has no irritating effect. In particular, the suspensions according to the invention contain from 0.1 to 5% and preferably from 0.5 to 2% by weight of NaCl.

The suspensions according to the invention are prepared by mixing the various constituents. In particular, it will be possible to operate as follows: obtaining a mixture of the amphiphilic compound A1, propylene glycol, surfactant (s), minoxidil, lipid matrix maintained at a temperature above its melting temperature, and optionally ethanol, - emulsification of the mixture obtained in water, solidification of the lipid nanoparticles obtained, by cooling.

The introduction of the amphiphilic compound A1, propylene glycol, surfactant (s), minoxidil and optionally ethanol into the lipid matrix can be carried out simultaneously. It is also possible that their introduction is done sequentially. For example, the amphiphilic compound A1, propylene glycol, the surfactant (s), and ethanol, when it is simultaneously present in the lipid matrix, may be added first and then the minoxidil maintaining the lipid matrix at a temperature above its melting temperature (for example greater than 5 to 10 ^° C. to prevent any degradation) and by homogenizing the mixture, by means of an appropriate technique, for example by means of a mechanical stirrer with propeller or blades. The water can then be added to the mixture obtained, maintained at a temperature above the melting temperature of the lipid matrix. Advantageously, the added water will also be at a temperature above the melting temperature of the lipid matrix, in order to prevent the solidification thereof as soon as the water is added. Instead of adding water to the mixture containing the other constituents, it is also possible to proceed in the opposite way.

When the suspension contains NaCl, it is, for example, added last. According to one embodiment of the invention, the mixing with water is carried out with stirring, by means of a suitable technique, for example by means of a mechanical propeller or blade stirrer. Then, the narrow size distribution of the solid lipid nanoparticles of the suspension is obtained either directly on the emulsion and therefore hot, or after solidification, on the nanoparticles. Indeed, a homogenization step is carried out, either with stirring at high speed and with heating, for example with a turbine stirrer such as an ultra-Turrax®, or with a high pressure homogenizer such as an Emulsiflex, with hot, or at room temperature. The solid lipid nanoparticles according to the invention are thus obtained in aqueous suspension which is in the form of a homogeneous mixture. The solid lipid nanoparticles are in the form of a relatively homogeneous solid matrix, in which the minoxidil is distributed: it is said that the minoxidil is encapsulated in the solid lipid nanoparticles, although the latter are not in the form of a capsule with heart / membrane structure. The concentration of minoxidil, in particular, may be adapted, depending on the intended application and, in particular, the chosen mode of administration. Depending on the viscosity of the suspension, the solid lipid nanoparticles will more or less tend to sediment. The composition according to the invention gives minoxidil a protection during its storage, as well as during its transport to its site of action. These solid lipid nanoparticles are therefore quite suitable for use as a colloidal system for vectorizing minoxidil. The compositions according to the invention may in particular be administered enterally, parenterally, or preferably topically.

It is also possible to lyophilize the aqueous suspension of nanoparticles obtained by any known technique. Such a freeze-dried composition may be directly used or redispersed in an aqueous phase to yield the desired composition, depending on the intended mode of administration. For example, it is possible to use the solid lipid nanoparticles in the form of a powder formulated in an aerosol with a suitable carrier gas, acting as a dispersing phase. The compositions according to the invention make it possible to obtain better penetration into the skin of minoxidil, in particular with respect to existing commercial compositions based on a large quantity of ethanol. This property is particularly advantageous because it allows the minoxidil to gain more easily its action site.

In addition, because of the combination of the various components used, it is possible to use reduced amounts of propylene glycol and ethanol, when present, which makes their use on the mucous membranes and the scalp, better tolerated. Indeed, a reduction in the amount of propylene glycol, relative to existing formulations reduces the sensitizing power of cosmetic or pharmaceutical compositions containing such suspensions or solid lipid nanoparticles.

The compositions according to the invention may also make it possible to modulate the release of minoxidil. Also, the solid lipidic suspensions and nanoparticles according to the invention can be used to fight against hair loss and / or promote their regrowth, in the form of a cosmetic or pharmaceutical composition. In particular, they may be in a form suitable for topical application, for example in the form of cream, gel, solution, aerosol or any other form suitable for topical application. Such compositions according to the invention may be used for the treatment of alopecia, in particular by promoting hair growth.

The following example illustrates the invention, but has no limiting character. EXAMPLE 1 a) The qualitative and quantitative composition of the aqueous suspension of solid lipid nanoparticles (named SLN of "solid lipid nanoparticles") loaded with minoxidil is given below: Suppocire® 5 g Phospholipon® 1.5 g

Minoxidil (case # 38304-91-5) 2.5 g

Propylene Glycol (Case # 57-55-6) 0.85g Montanox® 20 (case # 9005-64-5) 2 g

Montane® 80 (case # 1338-43-8) 3 g

Purified Water (Case # 7732-18-5) 35.1 g

Ethanol (case # 64-17-5) 0.05g In a first stage, the Suppocire® is melted at 40 ^° C. in a beaker. Phospholipon®, propylene glycol, Montanox® 20 ethanol and Montane® 80 are mixed with the molten Suppocire®, with stirring (25rpm), for 20 min at 40 ^° C. Minoxidil is added to this beaker . This mixture is left stirring (25 rpm) for 12 hours at 40 ^° C. The purified water is heated to 40 ^° C. and then added to the mixture with stirring (60 rpm). Stirring is maintained until the temperature of the mixture is lowered to 20 ^° C. Finally, the mixture is passed to the high pressure homogenizer (5 passages at 100,000 kPa).

The size of the SLNs, determined using a Zetamaster® S, is 200 nm. The concentration of minoxidil in the suspension was determined by high performance liquid chromatography and is 4.67% by mass. The pH of this suspension is 6.5. b) According to another embodiment, after adding the purified water, the mixture, at 40 ⁰ C, is passed to the high pressure homogenizer (5 passages at 100000 kPa). At the homogenizer outlet, the mixture is kept stirring (60 rpm) in a beaker. Stirring is maintained until the temperature of the mixture has dropped to 20 ^° C. The size of the SLN obtained and the yield of minoxidil are identical. c) According to another embodiment variant, in a first step, the Suppocire® is melted at 40 ^° C. in a beaker. Phospholipon®, propylene glycol, Montanox® 20 and Montane® 80 are mixed with the molten Suppocire®, with stirring (30 rpm), for 20 min at 40 ^° C. The minoxidil is added to this beaker. This mixture is left under stirring (30 rpm) for 12 hours at 40 ⁰ C. The purified water is heated to 40 ⁰ C and then added to the stirred mixture with a turbine (10,000 rpm). Stirring is maintained until the temperature of the mixture has dropped to 20 ⁰ C. The size of SLN obtained is then 300 nm, against the yield of minoxidil remains unchanged.

EXAMPLE 2 a) The qualitative and quantitative composition of the aqueous suspension of solid lipid nanoparticles (named SLN of "solid lipid nanoparticles") loaded with minoxidil is given below: Suppocire® 5 g

Phospholipon® 1.5 g Minoxidil (case # 38304-91-5) 2.5 g

Propylene Glycol (Case # 57-55-6) 0.85g

Montanox® 20 (case # 9005-64-5) 2 g

Montane® 80 (case # 1338-43-8) 3 g

Purified water (case # 7732-18-5) 34.65 g NaCl (case # 7647-14-5) 0.45g

Ethanot (case # 64-17-5) 0.05g

In a first step, the Suppocire® is melted at 40 ^° C. in a beaker. Phospholipon®, propylene glycol, Montanox® 20, ethanol and Montane® 80 are mixed with the molten Suppocire®, with stirring (25rpm), for 20 min at 40 ^° C. Minoxidil is added to this mixture. beaker. This mixture is left stirring (25 rpm) for 12 hours at 40 ^° C. NaCl is dissolved in purified water. The mixture is heated at 40 ^° C. and then added to the mixture of lipids with stirring (60 rpm). Stirring is maintained for 1 hour, at 40 ^° C. Finally, the mixture is passed to the high pressure homogenizer (5 passages at 100,000 kPa). b) According to another variant, after stirring (25 rpm), for 12 hours at 40 ^° C. of the mixture containing Suppocire®, Phospholipon®, propylene glycol, Montanox® 20, ethanol, Montane® 80 and the minoxidil, the purified water is heated to 40 ⁰ C and then added to the mixture with stirring (60 rpm). Stirring is maintained for one hour at 40 ^° C. Finally, the mixture is passed to the high pressure homogenizer (5 100,000 kPa). NaCl is added to the SLN slurry with magnetic stirring (50rpm). Stirring is now for 30 minutes.

The stability of the formulations with and without NaCl was studied according to a loop rheology test (with a coaxial cylinder geometry): starting at 25 ° C, descent to 10 ^° C., then rising to 25 ° C. constant shear 10s ^"1

The results are shown in the single figure.

Tolerance results = results of corrosivity tests:

The principle of the study is to evaluate the corrosive potential of the formulations by an ex-vivo method. Corrosivity is determined on pork ear skin. To validate the method, a negative control and a positive control are carried out under the same conditions.

The skin surface is treated with the formulation to be tested for 15 minutes. At the end of the treatment, the formulation is removed from the skin surface. A solution of Sulforhodamine B (a hydrophilic dye that labels cutaneous proteins) is then applied to the skin surface for 15 minutes. After 15 minutes, the Sulforhodamine B solution is removed using a syringe and then a swab. Finally, the skin surface is rinsed with 1 ml of 0.9% NaCl solution. The absorbance of the NaCl solution containing traces of Sulforhodamine B (Le. Sulforhodamine B initially adsorbed on the epidermal proteins) is determined spectrophotometrically at 565.5 nm.

• In the absence of a corrosive effect, the epidermal proteins are intact; the adsorption then the desorption of Sulforhodamine B is maximal. Sulforhodamine B, initially adsorbed on cutaneous proteins, is desorbed in the rinsing solution. The absorbance of the rinsing solution is therefore maximal.

• In the presence of a corrosive effect, the epidermal proteins are denatured. Sulforhodamine B can therefore enter the skin. During rinsing, little Sulforhodamine B is desorbed in the rinsing solution. The absorbance of the rinsing solution is therefore minimal.

Procedure for the determination of the corrosivity factor

^ Take a skin sample from an unshaven pig's ear with a scalpel and avoid injuring it. > Cut out skin samples the size of the donor compartment, then place them in Franz's cell so that the dermis is on the side of the recipient compartment.

> Fill the recipient compartment with a saline syringe with saline, being careful that there is no air bubble in contact with the dermis.

> Place the donor compartment of the cell on the epidermis and fix it with a Môhr forceps.

> Place the cells in a water bath at 37 ° C.

> Place 200μL of each formulation on the skin surface of each skin sample. > Leave in contact for 5 minutes. > Eliminate the formulations using a 1OmL syringe.

> Rinse twice with 1 ml of 0.9% NaCl (suction / discharge, several times on the surface of the skin).

> Add 0.5 ml of Sulforhodamine B to the cutaneous surface of each sample. ^ Leave in contact for 15 minutes.

> Remove the sulforhodamine solution from the skin surface with a syringe (remove remaining traces with a swab). > Add 1 ml of NaCl to the surface of each skin sample. > Then achieve 5 discharge aspirations of the NaCl solution. Recover the NaCl solution and transfer it to a micro-tank to measure the absorbance by UV spectrophotometer. > Measure the absorbance of the solutions at 565.5nm, after setting the zero on the initial NaCl solution. The corrosivity factor is determined by the following formula:

_J Abs Sample - A bs NaCl 0.9%

Corrosivity factor = - - -, - "

NaCI Abs 0.9%

If the corrosivity factor is greater than zero then the sample is non-corrosive.

If the corrosivity factor is less than zero then the sample is corrosive.

TABLE 1 shows the corrosivity factors of different formulations, the formulation of Example 1a). TABLE 1

The white SLN are prepared as in example la), but without minoxidil.

If the corrosivity factor is greater than zero then the sample is non-corrosive. If the corrosivity factor is less than zero then the sample is corrosive.

TABLE 2 represents the results of a statistical study on the corrosivity factor (Si t probability> 0.05, then the factors are statistically identical If t probability <0.05, then the factors are statistically different.) TABLE 2

White SLN suspension and loaded SLN suspension are not corrosive. The commercial solution Alopexy 5% is slightly corrosive but significantly less than nitric acid (positive control).

As a comparison of the NLCs were prepared according to the protocol described by A. C. Silva et al. supra. Although the protocol has been rigorously followed, the NLC loaded to 0.3% minoxidil obtained do not have the diameter announced in the publication. First, it should be noted that if the samples are not sonicated, it is very difficult or impossible to measure the diameter of the NLCs. After 5 minutes in the ultrasonic bath, the diameter of the uncharged NLCs and charged NLCs (0.3% minoxidil) is 450 nm ± 100 nm.

Due to hardware problems, the measurement of the corrosivity factor of the NLC loaded at 0.3% was adapted to the available equipment. The same test was performed but the results were interpreted with a chroma meter.

The color parameters are recorded in a system L *, a *, b * where a color is expressed vectorially in a system of 3 three-dimensional coordinates: a red-green axis (a *), a blue-yellow axis (b *) and a gloss axis (L *). The total variation of the color is expressed according to the following equation:

AE = _^ J Aa ^{* 2} + Ab ^{* 1} + AL ^{* 2} The results are shown in TABLE 3 below. TABLE 3

The higher the value of E, the more corrosive the sample tested.

In the same manner, the corrosivity factor of the formulation of Example 2a) was tested and the results are shown in TABLE 4 below.

TABLE 4

Claims

1 - Suspension of solid lipid nanoparticles in an aqueous phase in which: the solid lipid nanoparticles encapsulate minoxidil in a lipid matrix, and furthermore comprise at least one amphiphilic compound A1 chosen from phospholipids, and in particular from phosphatidylcholines and lecithins, propylene glycol, one or more surfactants and optionally ethanol, the aqueous phase contains water, propylene glycol and optionally ethanol.

2 - Suspension according to claim 1 characterized in that it contains from 0.1 to 10%, preferably from 3 to 7% by weight of minoxidil.

3 - Suspension according to claim 1 or 2 characterized in that it contains NaCl.

4 - Suspension according to claim 3 characterized in that it contains from 0.1 to 5% and preferably from 0.5 to 2% by weight of NaCl.

5 - Suspension according to one of the preceding claims characterized in that the lipid matrix comprises at least one lipid L1 selected from mono-, di- and triglycerides and does not include stearic acid.

6 - Suspension according to claim 5 characterized in that the lipid L1 is a mixture of triglycerides in

7 - Suspension according to claim 5 or 6 characterized in that the suspension comprises from 5 to 30%, preferably from 5 to 15% by weight of lipid L1.

8 - Suspension according to one of the preceding claims characterized in that the amphiphilic compound Al is a soy lecithin, consisting predominantly of phosphatidylcholines.

9 - Suspension according to one of the preceding claims characterized in that the suspension comprises from 1 to 10%, preferably from 1.5 to 5

% by weight of amphiphilic compound Al. 10 - Suspension according to one of the preceding claims characterized in that the suspension comprises 1 to 10%, preferably 1 to 5% by weight of propylene glycol.

11 - Suspension according to one of the preceding claims characterized in that the (s) surfactant (s) is (are) chosen from fatty acid esters of sorbitan and esters of fatty acids and sorbitan polyoxyethylene.

12 - Suspension according to one of the preceding claims characterized in that the surfactant or mixture of surfactants has an HLB in the range of 7.0 to 11.0, and preferably 8.5 to 9.5.

13 - Suspension according to one of the preceding claims characterized in that the suspension comprises 1 to 15%, preferably 8 to 12% by weight of surfactant (s).

14 - Suspension according to one of the preceding claims characterized in that the suspension comprises from 50 to 90%, preferably from 65 to 75

% by mass of water.

15 - Suspension according to one of the preceding claims characterized in that it contains from 0.1 to 2%, preferably from 0.1 to 0.5% by weight of ethanol. 16 - Suspension according to one of the preceding claims characterized in that the nanoparticles have a diameter in the range of 100 to 500 nm, preferably in the range of 150 to 300 nm.

17 - solid lipid nanoparticles encapsulating minoxidil in a lipid matrix, and further comprising at least one amphiphilic compound A1 chosen from phospholipids, and in particular from phosphatidylcholines and lecithins, propylene glycol, one or more surfactants and optionally ethanol.

18 - solid lipid nanoparticles according to claim 17 characterized in that the lipid matrix comprises at least one lipid L1 selected from mono-, di- and triglycerides and does not include stearic acid. 19 - Solid Lipid nanoparticles according to claim 18 characterized in that the Ll lipid is a mixture of triglycerides Cl ₂ - Ci _8.

Solid lipid nanoparticles according to claim 18 or 19, characterized in that they comprise from 35 to 80%, preferably from

35 to 55% by weight of lipid L1.

21 - solid lipid nanoparticles according to one of claims 17 to

Characterized in that the amphiphilic compound A1 is a soy lecithin, consisting predominantly of phosphatidylcholines. 22 - solid lipid nanoparticles according to one of claims 17 to

Characterized in that they comprise from 1 to 20%, preferably from 5 to 15% by weight of amphiphilic compound Al.

23 - solid lipid nanoparticles according to one of claims 17 to

Characterized in that they comprise from 0.1 to 2%, preferably from 0.1 to 0.75% by weight of propylene glycol.

24 - solid lipid nanoparticles according to one of claims 17 to

Characterized in that the surfactant (s) is (are) selected from fatty acid esters of sorbitan and esters of polyoxyethylenated fatty acids and sorbitan. Solid lipid nanoparticles according to one of claims 17 to

Characterized in that the surfactant or surfactant mixture has an HLB in the range of 7.0 to 11.0, and preferably 8.5 to 9.5.

26 - solid lipid nanoparticles according to one of claims 17 to 25 characterized in that they comprise from 5 to 45%, preferably from

10 to 30% by weight of surfactant (s).

27 - solid lipid nanoparticles according to one of claims 17 to

Characterized in that they comprise from 0.1 to 1.5%, preferably from 0.1 to 0.75% by weight of ethanol. 28 - solid lipid nanoparticles according to one of claims 17 to

Characterized in that they comprise from 1 to 30%, preferably from 15 to 29% by weight of minoxidil. 29 - solid lipid nanoparticles according to one of claims 17 to

Characterized in that the nanoparticles have a diameter in the range of 100 to 500 nm, preferably in the range of 150 to 300 nm. Solid lipid nanoparticles according to one of claims 17 to

29 characterized in that they are obtained by lyophilization of one of the suspensions according to one of the preceding claims.

31 - Cosmetic or pharmaceutical composition comprising a suspension according to one of claims 1 to 16 or solid lipid nanoparticles according to one of claims 17 to 30.

32 - cosmetic or pharmaceutical composition according to claim 31 for combating alopecia, promoting hair growth.

33 - Cosmetic or pharmaceutical composition according to claim 31 or 32, in a form suitable for topical application. 34 - Process for the preparation of a suspension according to one of claims 1 to 16 comprising the steps of: obtaining a mixture of the amphiphilic compound Al selected from phospholipids, and in particular from phosphatidylcholines and lecithins, with propylene glycol, the surfactant (s), the minoxidil, the lipid matrix maintained at a temperature above its melting temperature, and optionally ethanol, emulsification of the mixture obtained in water, solidification of the lipid nanoparticles obtained, by cooling.

35 - Process according to claim 34, characterized in that it comprises a homogenization step after emulsification.

36 - Process according to claim 35, characterized in that it comprises a homogenization step, after solidification. 37 - Process for preparing solid lipid nanoparticles according to one of claims 17 to 30 comprising the following steps: obtaining a mixture of the amphiphilic compound Al chosen from phospholipids, and in particular from phosphatidylcholines and lecithins, with propylene glycol, the surfactant (s), minoxidil, the lipid matrix maintained at a temperature above its melting temperature , and, optionally, ethanol, emulsification of the mixture obtained in water, solidification of the lipid nanoparticles obtained, by cooling, to lead to an aqueous phase suspension of solid lipid nanoparticles lyophilization of the suspension of solid lipid nanoparticles obtained.