FR2746009A1 - Stable vitamin A ester emulsions - Google Patents

Abstract

A stable emulsion of a Vitamin A ester is prepared by: (a) dissolving the ester in a cold mixture of an aqueous phase containing: (i) an alkylene glycol (especially propylene glycol); (ii) a polyol (especially glycerin); and (iii) a sorbitan oleate (especially sorbitan mono-oleate); and (b) mixing the solution in a warm fatty acid ester phase.

Description

 The present invention relates to a composition for topical use incorporating a precursor of vitamin A, and more particularly to a method for obtaining such a composition.

 The lack of vitamin A in the human body induces a hyperkeratinization of the epidermis which results in an increase in the thickness of the stratum corneum, which is at the root of many skin conditions such as acne.

 Vitamin A, applied topically, exerts an action on the epidermis, on the one hand, by softening the stratum corneum and decreasing its thickness, and on the other hand, by causing hyperplasia in the layers of proliferative basal cells which manifests itself in an overall thickening of the epidermis, but it also exerts a beneficial action on the dermis by increasing the synthesis and the renewal of collagen and elastin networks by increasing the fibroblastic activity, and inhibition of the collagenous activity.

 Vitamin A is thus used to treat skin conditions related to hyperkeratinization, but also to combat the effects of aging skin by "filling" superficial wrinkles.

 The active form of vitamin A is in fact vitamin A acid or retinoic acid, but other active forms are known, in particular retinal esters or esters of vitamin A. Some retinal esters are capable of increasing the multiplication of cells. epidermal and inhibit the formation of the stratum corneum.

The difficulty encountered in the use of vitamin esters
A in cosmetic compositions results from the physicochemical instability of these emulsion esters, in particular in the case of vitamin A acetate.

 The Applicant has developed a simple method for obtaining a stabilized emulsion of a vitamin A ester.

 Thus, the first object of the invention is a process for preparing a stable emulsion of a vitamin A ester, comprising the step of cold solubilizing said ester in an aqueous phase (i) of alkylene glycol, in particular propylene glycol (2) polyol, in particular glycerine and (3) sorbitan oleate, in particular sorbitan mono-oleate, and then hot mixing, preferably at a temperature not exceeding 40 OC, the solution obtained in a phase of esters of fatty acids. This process is particularly suitable for the solubilization and stabilization in emulsion of vitamin A acetate, practically insoluble in water and alcohols.

 According to one variant of the process of the invention, an emulsion of a stabilized vitamin A ester, in the encapsulated form, is obtained by proceeding before the step of cold solubilization of the ester, to its encapsulation. This step consists in cold dispersing and stirring said ester in a fraction of soy lecithins and / or vegetable ceramides, in which, preferably, the proportions of soy lecithins and vegetable ceramides are substantially equivalent.

 A second subject of the invention is a composition for topical use comprising a vitamin A ester, which advantageously consists of vitamin A acetate, obtained according to the previously defined process.

 The vitamin A ester will preferably be encapsulated in liposomes, so as to protect the active ingredient to its target.

 An advantageous composition of the invention further comprises a glycyrrhetinic derivative, preferably chosen from 18P-glycyrrhetinic acid, stearyl glycyrrhetinate, monoammonium glycyrrhizinate, potassium glycyrrhizinate, dipotassium glycyrrhizinate and glycyrrhizinic acid. 18 P-glycyrrhetinic acid is a preferred derivative.

 By combining the vitamin A ester and in particular the acetate with a glycyrrhetinic derivative, the Applicant has developed an effective composition but very well supported by the skin, as will be demonstrated later in the description.

 An even more advantageous composition of the invention comprises, in addition to the glycyrrhetinic derivative, a mixture of at least one α-hydroxylated acid and at least one β-hydroxylated acid. The α-hydroxy acid or acids may be selected from glycolic acid and lactic acid, and the β-hydroxy acid or acids may be selected from salicylic acid and serine.

 In fact, the α-hydroxylated acids have, in high doses, an exfoliating action on the epidermis leading to a decrease in the stratum corneum and a specific action on the synthesis of collagens. At these concentrations, these acids are usually irritating.

The combined use of ss-hydroxy acids also having an exfoliating action makes it possible to potentiate the effect of the α-hydroxy acids, that is to say with equal effectiveness makes it possible to reduce the proportion of α-hydroxyl acids in the composition. The local tolerance of the compositions is thus greatly improved without impairing their effectiveness.

 The ss-hydroxy acids also have antiseptic properties that enhance the action of preservatives, to limit their concentration of use.

 The incorporation of α-hydroxy acids in a composition of the invention is very advantageous because they complement, by their action on the stratum corneum, the preventive or curative action of the retinal ester.

The various constituents of a preferred composition according to the invention, formulated in a suitable excipient, and their proportions (expressed in percent relative to the weight of the composition) are given below
Solubilized vitamin A ester
Vitamin A Acetate (1 million units per ml) 0.15 - 2.00
Propylene glycol 0.20 - 0.60
Glycerin 0,20 - 0,60
Demineralized water 0.15 - 0.40
Mono-Oleate of Sorbitan (20 OE) 0.60- 1.80
3-9 fatty acid esters (2-ethylhexyl-palmitate / stearyl heptanoate)
Butyl-hydroxy-anisole (BHA) or butyl-hydroxy-toluene (BHT) 0.02 - 0.05
Α-hydroxylated acids
glycolic acid or lactic acid 1 - 10
Ss-hydroxylated acids
Salicylic acid 0.5 - 3.0
Glvcvrrhetiniae derivative
Beta-glycyrrhetinic acid 18 1-5
The compositions of the invention can be used in all the indications for which vitamin A is effective, in prevention and in care, and in particular in the care of skins suffering from hyperkeratinization and the care of aged skin.

 Finally, a final subject of the invention concerns any preparation obtained by formulation of a composition of the invention, such as a cream. In order to preserve the preparation and in particular protect the vitamin A ester against oxidation, the preparation is advantageously carried out and packaged under vacuum.

EXAMPLE 1 Physico-chemical stability tests of various vitamin A derivatives in emulsions obtained according to the process of the invention
Table I below summarizes the results of the assays performed by the UV-visible spectrophotometry and high performance liquid chromatography techniques performed on different emulsions obtained according to the process of the invention and at different storage times in a standard packaging and at 50 OC (unless otherwise stated).

 The results of the assays show a higher stability of the vitamin A acetate, especially at high temperature at 500C.

TABLE I

VITAMIN <SEP> A <SEP> VITAMIN <SEP> A <SEP> VITAMIN <SEP> A <SEP> VITAMIN <SEP> A <SEP> RETINOL
<tb> ACID <SEP> PALMITATE <SEP> ALDEHYDE <SEP> ACETATE <SEP> ALL <SEP> TRANS
<tb> QUANTITY <SEP> DOSSE <SEP> AU <SEP> START <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l
<tb> QUANTITY <SEP> PRESENT <SEP> A <SEP> ANALYSIS <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l <SEP > 10 <SEP> mg / l <SEP> 10 <SEP> mg / l
<tb> AFTER <SEP> 7 <SEP> DAYS <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l
<tb> PERCENTAGE <SEP> OF <SEP> LOSS <SEP> 0% <SEP> 0% <SEP> 0% <SEP> 0% <SEP> 0%
<tb> AFTER <SEP> 15 <SEP> DAYS <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l <SEP> 10 <SEP> mg / l
<tb> PERIODS <SEP> OF <SEP> LOSS <SEP> 0% <SEP> 0% <SEP> 0% <SEP> 0% <SEP> 0%
<tb> AFTER <SEP> 34 <SEP> DAYS <SEP> 9.8% <SEP> mg / l <SEP> 10 <SEP> mg / l <SEP> 8.4 <SEP> mg / l <SEP><SEP> mg / l <SEP> 9.7 <SEP> mg / l
<tb> PERCENTAGE <SEP><SEP> LOSS <SEP> 2% <SEP> 0% <SEP> 16% <SEP> 0% <SEP> 3%
<tb> AFTER <SEP> X <SEP> DAYS <SEP>&num;<SEP> 9.5 <SEP> mg / l <SEP>&num;<SEP> 0 <SEP> mg / l <SEP>#<SEP> 3.0 <SEP> mg / l <SEP>&num;<SEP> 7.1 <SEP> mg / l <SEP>&<SEP> 4.6 <SEP> mg / l
<tb> PERCENTAGE <SEP><SEP> LOSS <SEP> 5% <SEP> 100% <SEP> 70% <SEP> 29% <SEP> 54%
<tb> APPES <SEP> 48H <SEP> A <SEP> 50C <SEP> 1.8 <SEP> mg / l <SEP> 7 <SEP> mg / l <SEP> 6.1 <SEP> mg / <SEP> 9.1 <SEP> mg / l <SEP> 0.8 <SEP> mg / l <SEP> *
<tb> PERCENTAGE <SEP><SEP> LOSS <SEP> 82% <SEP> 30% <SEP> 39% <SEP> 9% <SEP> 92%
<tb> AFTER <SEP> 7J <SEP> AT <SEP> 50 C <SEP> 1.3 <SEP> mg / l <SEP> 2.6 <SEP> mg / l <SEP> 3.1 <SEP> mg / l <SEP><SEP> 6.4 <SEP> mg / l <SEP> 0.2 <SEP> mg / l <SEP> **
<tb> PERCENTAGE <SEP><SEP> LOSS <SEP> 87% <SEP> 74% <SEP> 69% <SEP> 36% <SEP> 98%
<tb>&num; corresponds to an assay performed at 8.5 months at room temperature, corresponds to an assay performed at 5.5 months at room temperature, and corresponds to an assay performed at 4.25 months at room temperature.

EXAMPLE 2 Influence of various factors namely encapsulation of vitamin A acetate, the presence of an antioxidant and conditioning, on emulsion stability
Different compositions A to K are prepared according to the method of the invention and contain 0.7% by weight of vitamin A acetate (1 million units per ml) relative to the total weight of the composition.

 The results appearing in Table II below show the favorable influence of the encapsulation of the vitamin A ester, of a conditioning in the absence of air, of the antioxidant, on the stability of a composition.

TABLE II

<tb> Sample <SEP> Antioxidant <SEP> Vectorization <SEP> Condt. <SEP> Temperature <SEP> Time <SEP> days <SEP>% <SEP> loss
<tb><SEP> A <SEP> 0 <SEP> NO <SEP> POT <SEP> 500C <SEP> 30 <SEP> 86
<tb><SEP> B <SEP> O <SEP> NO <SEP> AIKLESS <SEP> sooc <SEP> 30 <SEP> 52
<tb><SEP> C <SEP> O <SEP> YES <SEP> AIRLESS <SEP> 50 C <SEP> 30 <SEP> 48
<tb><SEP> D <SEP> 0.01 <SEP> NO <SEP> POT <SEP> 50 C <SEP> 30 <SEP> 7t <SEP>
<tb><SEP> E <SEP> 005 <SEP> NO <SEP> POT <SEP> 50 C <SEP> 30 <SEP> 64
<tb><SEP> F <SEP> 0.05 <SEP> YES <SEP> POT <SEP> 50 C <SEP> 30 <SEP> 60
<tb><SEP> g <SEP> 0.05 <SEP> YES <SEP> AIRLESS <SEP> 50 C <SEP> 30 <SEP> 35
<tb><SEP> H <SEP> 0 <SEP> NO <SEP> POT <SEP> 400C <SEP> 30 <SEP> 68
<tb><SEP> 1 <SEP> 0.05 <SEP> YES <SEP> AIRLESS <SEP> 40 C <SEP> 30 <SEP> 17
<tb><SEP> J <SEP> 0 <SEP> NO <SEP> POT <SEP> TA <SEP> 365 <SEP> 42
<tb><SEP> K <SEP> 0.05 <SEP> YES <SEP> AIRLESS <SEP> TA <SEP> 30 <SEP> 1-2
<Tb>
Example 3 Demonstration of the Soothing Role of a Derivative of Glycyrrhetinic Acid in a Preparation of the Invention
This role is illustrated by the following test consisting in comparing the local tolerance of two care creams K and L of the invention, cream K also incorporating 18P-glycyrrhetinic acid.

a) Formulation of K and L care creams
Cream K:
Components of the excipient
Demineralized water qs 10
Vaseline 10
Silicones 6
Stearic acid 0.3
Triethanolamine i
Panthenol 0.5
Polymers of acrylic acid 0.35
Glycerol stearate 3
Solubilized vitamin A ester
Vitamin A acetate 1
Propylene glycol 0.20 - 0.60
Glycerin 0,20 - 0,60
Demineralized water 0.15 - 0.40
Sorbitan mono-oleate (20 EO) 0.60 - 1.80
3-9 fatty acid esters (2-ethylhexyl-palmitate / stearyl heptanoate)
BHA or BHT 0.02 - 0.05
Glvcyrrhetiniae derivative
Beta-glycyrrhetinic acid 18 2
conservatives
Phenoxyethanol, 0.82 Parabens
The care cream L responds to the same formulation with the difference that it does not contain beta-glycyrrhetinic acid.

b) Test conditions
The test is performed on two groups of 20 women according to a mode of application performed in the morning and in the evening on previously cleansed skin.

The recommended duration of use is 5 days.

c) Results
The results are expressed on the basis of 36 exploitable responses, ie 90%.

Table III below shows the distribution of tolerance assessments for the two K and L creams.

Table III

<tb><SEP> GROUP <SEP> K <SEP> GROUP <SEP> L
<tb><SEP> Number <SEP> 96 <SEP><SEP> Number
<tb> VERY <SEP> WELL <SEP> TOLERATED <SEP> 13 <SEP> 72 <SEP> O <SEP> O
<tb> WELL <SEP> TOLERATED <SEP> 5 <SEP> 28 <SEP> 2 <SEP> 11
<tb> AVERAGE <SEP> WELL <SEP> TOLERATED <SEP> O <SEP> 11 <SEP> 61
<tb> NOT <SEP> VERY <SEP> WELL <SEP> TOLERATED <SEP> ~ <SEP> 5 <SEP> 28
<tb> VERY <SEP> MAL <SEP> TOLERATED <SEP> O <SEP> O <SEP> O <SEP>
<tb> d) Discussion
All women in group K who used the cream with the glycyrrhetinic derivative tolerated or tolerated the product well.

 None of the women in the L group who used the cream tolerated the product very well (61% of them only slightly tolerated).

 The rate of favorable and statistically significant comments is therefore much higher for group K than for group L.

 It can therefore be concluded that the glycyrrhetinic derivative has a beneficial effect on the local tolerance of the product.

EXAMPLE 4 Demonstration of the Efficacy of a Preparation of the Invention Incorporating Both the Vitamin A Ester, a Glycyrrhetinic Acid Derivative and a Mixture of α-Hydroxy Acid and Ss Acid - hydroxylated
This role is illustrated by the following test consisting of comparing the effectiveness of four care creams M, N, O and P of the invention.

a) Formulation of care creams M, N, O and P
These four formulations differ in the presence or absence of one or more of the following four components: α-hydroxyl acids, s-hydroxyl acids, vitamin A acetate and glycyrrhetinic acid derivative.

Comoosants of the excipient
Demineralized water qs 100
Propylene glycol 7 - 9
Cationic acrylic homopolymer 3 - 5
(in dispersion in the oil)
0.05 yellow iron oxide
Α-hydroxy acids
glycolic acid or lactic acid
B-hydroxy acids
Salicylic acid
Solubilized vitamin A ester
Vitamin A acetate
Propylene glycol 0.20 - 0.60
Glycerine 0,20- 0,60
Demineralized water 0.15 - 0.40
Mono-Oleate of Sorbitan (20 OE) 0.60- 1.80
Fatty acid esters 3 - 9 (ethyl-2-hexylhexitate / cetearyl heptanoate)
BHA or BHT 0.02 - 0.05
Glucose derivative
18 beta-glycyrrhetinic acid
conservatives
Sodium parabens 0.30
The care cream M contains only one of the 4 constituents mentioned above, namely 10% of glycolic acid.

The care cream N contains 2 of the 4 constituents mentioned above, 5% of glycolic acid and 0.5% of salicylic acid.

Care cream O contains 3 of the above 4 components, 5% glycolic acid, 0.5% salicylic acid and 0.5% vitamin A acetate
Care cream P contains the above-mentioned 4 components, 5% glycolic acid, 0.5% salicylic acid, 0.5% vitamin A acetate and 2.5% beta-glycyrrhetinic acid.

b) Test conditions
The test is performed on four groups of 20 women according to a mode of application performed in the evening on perfectly cleansed skin before.

The recommended duration of use is 10 days.

c) Results
The results are expressed on the basis of 72 usable responses, ie 90%.

Table IV below shows the distribution of the efficacy evaluations for the four creams M, N, O, P. Specifically, it was asked to assess the beneficial effect of the cream on the radiance of the complexion and the attenuation of fine lines.

Table IV

<tb><SEP> Group <SEP> M <SEP> Group <SEP> N <SEP> Group <SEP> O <SEP> Group <SEP> P
<tb><SEP> Nb <SEP>% <SEP> Nb <SEP>% <SEP> Nb <SEP>% <SEP> Nb <SEP>%
<tb> TREKS <SEP> GOOD <SEP> 3 <SEP> 15 <SEP> 2 <SEP> 13 <SEP> 4 <SEP> 21 <SEP> 4 <SEP> 22
<tb> GOOD <SEP> 7 <SEP> 35 <SEP> 5 <SEP> 33 <SEP> 6 <SEP> 32 <SEP> 5 <SEP> 28
<tb> PLOT <SEP> GOOD <SEP> 4 <SEP> 20 <SEP> 3 <SEP> 21 <SEP> 5 <SEP> 26 <SEP> 6 <SEP> 33
<tb> NI <SEP> GOOD, <SEP> NI <SEP> WRONG <SEP> 3 <SEP> 15 <SEP> 2 <SEP> 13 <SEP> 2 <SEP> 10 <SEP> 1 <SEP> 6
<tb> WRONG <SEP> WRONG <SEP> 1 <SEP> 5 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0
<tb> BAD <SEP> o <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0
<tb> VERY <SEP> BAD <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0
<tb> NO <SEP> OPINION <SEP> 2 <SEP> 10 <SEP> 3 <SEP> 20 <SEP> 2 <SEP> 11 <SEP> 2 <SEP> 11
<Tb>
Table V below shows the distribution of the tolerance assessments of the four creams M, N, O and P.

Table V

<tb><SEP> Group <SEP> M <SEP> Group <SEP> N <SEP> Group <SEP> O <SEP> Group <SEP> P
<tb><SEP> Nb <SEP>% <SEP> Nb <SEP>% <SEP> Nb <SEP>% <SEP> Nb <SEP>%
<tb> VERY <SEP> WELL <SEP> TOLERATED <SEP> o <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 3 <SEP> 17
<tb> BIENTOLEREE <SEP> 3 <SEP> 15 <SEP> 5 <SEP> 33 <SEP> 3 <SEP> 16 <SEP> 8 <SEP> 44
<tb> MEDIUM <SEP> WELL <SEP> 9 <SEP> 45 <SEP> 6 <SEP> 40 <SEP> 7 <SEP> 37 <SEP> 5 <SEP> 28
<tb> TOLEREE
<tb> PASTRESBIENTOLEREE <SEP> 7 <SEP> 35 <SEP> 3 <SEP> 20 <SEP> 7 <SEP> 37 <SEP> 2 <SEP> 11
<tb> VERY <SEP> MALTOLEREE <SEP> 1 <SEP> 5 <SEP> 1 <SEP> 7 <SEP> 2 <SEP> 10 <SEP> 0 <SEP> 0
<tb> d) Discussion
It emerges from this sensory evaluation study that:
- Cream M, containing 10% glycolic acid alone, is considered effective on improving the radiance of the complexion and the attenuation of fine lines while being moderately well tolerated
- the cream N, better tolerated than the previous one, is considered just as effective, confirming the potentiation of the effects of glycolic acid by salicylic acid
cream 0, the most effective in this study, is also the least well tolerated; In this case, vitamin A acetate appears to reinforce the effectiveness of the other active ingredients, to the detriment of the local tolerance of the products.
cream P corresponds to the best compromise efficiency / tolerance with a comparable action to creams M and O, without their characteristic side effects in terms of cutaneous discomfort reactions.

Claims (20)

 1. Process for preparing a stable emulsion of a vitamin A ester, characterized in that said ester is cold-solubilized in an aqueous phase (1) of alkylene glycol, in particular propylene glycol, (2) polyol, in particular glycerin and (3) sorbitan oleate, in particular sorbitan mono-oleate, and the solution obtained is then hot-blended in a fatty acid ester phase.  2. Method according to claim 1, characterized in that the hot mix is carried out at a temperature not exceeding 400 C.  3. Process for preparing a stable emulsion of a vitamin A ester, in the encapsulated form, characterized in that it is dispersed cold and with stirring to encapsulate said ester in a fraction of soy lecithins and / or vegetable ceramides, said encapsulated ester is then solubilized in an aqueous phase of propylene glycol, of glycerol and of sorbitan mono-oleate, and the solution obtained is hot-blended in a fatty acid ester phase.  4. Process according to claim 3, characterized in that the weight proportions respectively of the vitamin A ester and the fraction of soy lecithins and / or vegetable ceramides are substantially equivalent.  5. Method according to one of the preceding claims, characterized in that the vitamin A ester is vitamin A acetate.  6. Composition for topical use comprising a vitamin A ester, characterized in that it consists of an emulsion of a vitamin A ester obtained by the process according to any one of claims 1 to 5.  7. Composition according to claim 6, characterized in that the ester is vitamin A acetate.  8. Composition according to claim 7, characterized in that it comprises vitamin A acetate in a proportion of between 0.15 and 2.00% by weight relative to the weight of the composition.  9. Composition according to one of claims 3 to 5, characterized in that the vitamin A ester is encapsulated in liposomes.  10. Composition according to any one of claims 6 to 9, characterized in that it further comprises a glycyrrhétinique derivative.  11. Composition according to Claim 10, characterized in that the glycyrrhetinic derivative is chosen from 188-glycyrrhetinic acid, stearyl glycyrrhetinate, monoammonium glycyrrhizinate, potassium glycyrrhizinate, dipotassium glycyrrhizinate and glycyrrhizinic acid.  12. The composition according to claim 11, characterized in that the glycyrrhetinic derivative is 18ss-glycyrrhetinic acid.  13. The composition of claim 12, characterized in that the proportion of 18-glycyrrhétinique acid is between 1 and 5.00% by weight relative to the weight of the composition.  14. Composition according to claims 8 and 13, characterized in that it comprises 2% of vitamin A acetate and 5% of 18ss-glycyrrhétinique acid.  15. Composition according to any one of claims 6 to 14, characterized in that it further comprises a mixture of at least one hydroxylated acid and at least one ss-hyd roxylé acid.  16. Composition according to Claim 15, characterized in that the acid or the hydroxylated acids are chosen from glycolic acid and lactic acid, and the acid or the n-hydroxylated acids are chosen from salicylic acid and serine.  17. A composition according to claim 15 or 16, characterized in that the proportion of the acid or of the hydroxy acids is between 1 and 10% by weight, and that of the acid or ss-hydroxy acids is between 0 and 10% by weight. , 50 to 3.00% by weight, relative to the weight of the composition.  18. Composition according to any one of claims 6 to 17, characterized in that it comprises 0.20 to 0.60% by weight of propylene glycol, 0.20 to 0.60% by weight of glycerine, 0, 60 to 1.80% by weight of sorbitan mono-oleate, 3.00 to 9.00% by weight of fatty acid esters, and 0.02 to 0.05% by weight of butyl-hydroxyanisole.  19. Cosmetic preparation comprising a composition according to any one of claims 6 to 18.  20. Preparation according to claim 19, characterized in that it is obtained and packaged under vacuum.