Azeco Cosmeceuticals

Formulations

15. Question: How to formulate a peeling with 10-15 % Azelaic acid? The final product should be a liquid or a gel. Answer: Azelaic acid is poorly soluble in water (2.1 g/l [20ºC]). The solubility increases with (partial neutralisation). Azelaic acid is a diprotic acid, with pKA1= 4,55 and pKA2=5,50. The solubility of disodium azelate is quite good: dissolved in water a translucent solution will be obtained. However, the pH of disodium azelate solutions is rather high (>7,0).

To dissolve a relatively high concentration Azelaic acid requires a thorough choice of the solvent(s)/emollient(s). There are several possibilities to achieve proper dissolution.

1. Probably the best solvent for Azelaic acid is ethoxydiglycol (diethylene glycol monoethyl ether). The solubility of Azelaic acid in ethoxydiglycol is better than 250 g/l. However, according to EU Regulation 1223/2009 this solvent is subject to concentration limitations (page 291, item #297). In cosmetic & personal care stay-on products only 2,6%. For medical devices and/or pharmaceutical products a higher concentration ethoxydiglycol is not a constraint. Ethoxydiglycol is commercially available from Gattefossé as Trans cutol® P. 2. The solubility of disodium azelate is relatively high (~180 g/l), but this results in a relatively high pH. For personal care pre parations this is considered as less appropriate. Neutralisation with a weak organic base leads to a lower pH value that simultaneously acts as a pH buffer. To be mentioned are TRIS (2-amino-2- (hydroxymethyl)propaan-1,3-diol) or AMP (aminomethyl propanol), both are available as a pharmaceutical grade. An even more elegant method is by using amino acids, more particularly arginine (2-amino-5- guanidinopentanoic acid) that also aids in wound healing. 3. The use of aminosugars, glucosamine being an exponent thereof, is a very elegant method as well, using a natural product that also enables irritation quenching. A cheap and effective method. In emulsion systems particular emollients may beneficially be used as well, more particularly the used of dimethyl or diisopropyl esters of adipic or sebacic acid. These are also powerful solvents that enhance the solubility of Azelaic acid. Particular attention shall also be given to triglycol ethyl ether, PPG-2 methyl ether acetate. propylene glycol butyl ether and propylene glycol propyl ether. These products are known with their tradename Dowanol®, commercially made available from DOW Chemical. Finally, the use of micro-emulsions base on polyglyceryl ethers is recommended, such as {polyglyceryl-4 laurate + isopropyl palmitate + demineralised water + pentylene glycol}, whereby polyglyceryl-4 oleate is a good alternative for polyglyce ryl-4 laurate. This system enables even to dissolve hard-to-dissolve ceramides. 16. Question: Can you recommend some formulation concepts? Answer: Formulation for skincare, (serum, geld, cream, lotion) shampoo & lotion and high dosage. We would like to refer to the Azepur99® skincare and haircare brochure. Here, all ingredients are presented and can be requested. 17. Question: We have taken trials with Azepur99® and we have observed crystallization in the formula. At the time of addition we are following the process as per the guidelines procedure given in the formulations from the skincare information file. Answer: Try to decrease the water content, substituting part of it with propylen/butylen glycol and a more polar emollient (synthetic esters with a better affinity with azelaic acid).

Mussenberg 1 • 6049 GZ Herten • The Netherlands

12