Preparation Of Azelaic Acid Ion-pairs And Its In Vitro Percutaneous Research On Penetration Mechanism

Azelaic acid is a natural saturated straight-chain dicarboxylic acid in animals and plants,which has the pharmacological effects of antibacterial,anti-inflammatory and competitive inhibition of tyrosinase activity.It is usually applied topically to the skin through external preparation to treat skin conditions such as acne,rosacea and hyperpigmentation.However,due to the barrier function of the stratum corneum of the skin and the characteristics of azelaic acid itself with high melting point and low water solubility,it is difficult to penetrate the stratum corneum to penetrate deeper layers of skin such as epidermis and dermis,resulting in low bioavailability.If high concentrations of azelaic acid are added to topical formulations,it can cause local irritation of the skin.Therefore,it is necessary to improve the physicochemical properties of azelaic acid without changing its structure to increase its solubility and permeability through the skin barrier.In this project,azelaic acid and various organic amines were prepared into ion-pairs,and the changes of their physical and chemical properties were studied.The effect of ion-pair and penetration enhancer on the skin permeability of azelaic acid was studied by in vitro percutaneous penetration method,and the permeation mechanism of azelaic acid ion-pair was discussed with molecular simulation technology.First,the percutaneous physicochemical properties of azelaic acid and its ion-pairs were studied.The blends of azelaic acid and various organic amines were simulated by using the Blends module of molecular simulation,and ethylamine,ethanolamine,n-hexylamine,laurylamine were selected as the paired organic amines to form ion pairs with azelaic acid.The ion-pair complexes of azelaic acid and the preferred organic amine were prepared in molar ratios of 1:1 and 1:2,respectively,and their characterization was performed.The results showed that azelaic acid and the preferred organic amine formed an ion pair through hydrogen bonding..The percutaneous physical and chemical properties of azelaic acid and its ion-pairs were measured,and it was found that the melting point of the ion-pair was lower than the melting point of azelaic acid.Then,the effects of the formation of ion-pairs and the addition of penetration enhancers on the skin permeability of azelaic acid were studied,and it was found that the penetration effect of azelaic acid was enhanced after the formation of ion-pairs.And the ion formed by azelaic acid and organic amine in a molar ratio of 1:2 is better than the ion formed by the same organic amine in a molar ratio of 1:1.Among the ion pairs of azelaic acid,AZA-N₆（1:2）had the best transdermal effect,and its ER value was 1.37.Combined with molecular simulation,the permeation mechanism of ion pair was discussed at the molecular level,and it was found that its potential mechanism of promoting penetration effect was to improve the compatibility with the stratum corneum.The effects of penetration enhancers on azelaic acid and its ion pair in vitro were studied,and it was found that terpinolene and azone had a certain penetration enhancement effect on azelaic acid,while oleic acid and isopropyl myristate had the opposite effect.to inhibition.The addition of the penetration enhancers isopropyl myristate,terpinolene,oleic acid,and azone reduced the skin permeability of AZA-N6（1:2）ion-pair,indicating that these four penetration enhancers do not Suitable for use in combination with ion-pair AZA-N₆（1:2）.