title: Nanocrystals of medium soluble actives--novel concept for improved dermal delivery and production strategy.
abstract: After use in oral pharmaceutical products, nanocrystals are meanwhile applied to improve the dermal penetration of cosmetic actives (e.g. rutin, hesperidin) and of drugs. By now, nanocrystals are only dermally applied made from poorly soluble actives. The novel concept is to formulate nanocrystals also from medium soluble actives, and to apply a dermal formulation containing additionally nanocrystals. The nanocrystals should act as fast dissolving depot, increase saturation solubility and especially accumulate in the hair follicles, to further increase skin penetration. Caffeine was used as model compound with relevance to market products, and a particular process was developed for the production of caffeine nanocrystals to overcome the supersaturation related effect of crystal growth and fiber formation - typical with medium soluble compounds. It is based on low energy milling (pearl milling) in combination with low dielectric constant dispersion media (water-ethanol or ethanol-propylene glycol mixtures) and optimal stabilizers. Most successful was Carbopol(®) 981 (e.g. 20% caffeine in ethanol-propylene glycol 3:7 with 2% Carbopol, w/w). Nanocrystals with varied sizes can now be produced in a controlled process e.g. 660 nm (optimal for hair follicle accumulation) to 250 nm (optimal for fast dissolution). The short term test proved stability over 2 months of the present formulation being sufficient to perform in vivo testing of the novel concept.
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutics, Biopharmaceutics & NutriCosmetics, Freie Universität Berlin, Kelchstr. 31, Berlin 12169, Germany. Electronic address: xuezhenzhai@hotmail.com.
authors.forename: Xuezhen
authors.initials: X
authors.lastname: Zhai
authors.affiliation: Department of Dermatology, Venerology and Allergology, Center of Experimental and Applied Cutaneous Physiology (CCP), Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, Berlin 10117, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Lademann
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutics, Biopharmaceutics & NutriCosmetics, Freie Universität Berlin, Kelchstr. 31, Berlin 12169, Germany; Fachhochschule/University of Applied Sciences Kaiserslautern, Carl-Schurz-Str. 10-16, Pirmasens 66953, Germany.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Keck
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutics, Biopharmaceutics & NutriCosmetics, Freie Universität Berlin, Kelchstr. 31, Berlin 12169, Germany. Electronic address: nanoteam@gmx.com.
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Müller
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D000279:Administration, Cutaneous; D002110:Caffeine / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D003358:Cosmetics; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D004339:Drug Compounding; D018859:Hair Follicle / Q000737:chemistry; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D012869:Skin Absorption; D012995:Solubility
chemical_list: D000180:Acrylic Resins; C516894:Carbopol 981; D003358:Cosmetics; D004337:Drug Carriers; D002110:Caffeine
keywords: Caffeine (PubChem CID: 2519); Dermal application; Ethanol (PubChem CID: 702); Hair follicle accumulation; High pressure homogenization; Nanocrystals; Pearl milling; Penetration enhancement; Propylene glycol (PubChem CID: 1030)