Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement by Nina Dragicevic & Howard I. Maibach

Author:Nina Dragicevic & Howard I. Maibach
Language: eng
Format: epub
Publisher: Springer Berlin Heidelberg, Berlin, Heidelberg

11.3 Role of Anti-nucleant Polymers

Supersaturated systems, by definitions, are unstable in their native state. In order to stabilize a supersaturated system and to achieve effective transdermal enhancement, it is absolutely crucial to keep the process of crystal formation to its minimum. For this purpose, anti-nucleant polymers are used in the supersaturated system. Some of the common polymers used as effective anti-nucleants are hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol (PEG), and Eudragits (acrylic polymers). These polymers have been shown to inhibit the crystal growth of compounds like paracetamol, nifedipine, spironolactone, sulfamethiazole, hydroflumethiazide, n-paraffin, estradiol, and griseofulvin from supersaturated solutions in a particular solvent and delivery systems (Simonelli et al. 1970; Corrigan and Timoney 1975; Sekikawa et al. 1978; Holden 1979; Hasegawa et al. 1985; Femi-Oyewo and Spring 1994; Kotiyan and Vavia 2001; Valenta and Auner 2004). Use of copolymers of methacrylic acid (Eudragit® E, EuE, and Eudragit® RL, EuRL) as ibuprofen crystal inhibitors in the matrices was found to prevent the drug crystallization for more than 12 months (Cilurzo et al. 2005). In another study, supersaturated solutions of ibuprofen were prepared using 25 % PG, 5 % vitamin ETPGS (d-alpha tocopheryl polyethylene glycol 1,000 succinate), and 5 % ethylene oxide/propylene oxide block copolymer (pluronic F127) solvents and their combinations to achieve different DS (0.5, 1, 2.5, 5.0, 10.0, 25.0, and 50), and it was found in that study that vitamin ETPGS improved the flux better compared to PG and pluronic F127. The optimization of the vitamin ETPGS/ibuprofen formulation with polymeric stabilizers like HPMC and PVP K-30 resulted in inhibiting crystal growth (HPMC showed better crystal growth inhibition compared to that of PVP K-30). However, the use of PVP K-30 increased the permeation rate of drug through the skin relative to the HPMC (Ghosh and Michniak-Kohn 2012).

How to select an appropriate polymer for a particular drug-solvent system is of a concern. The concept of nucleation and crystallization is not completely understood but efforts have been made to study the process using techniques like differential scanning calorimetry (DSC). In a study involving isothermal crystallization of lidocaine (LC) in supersaturated polyacrylate pressure-sensitive adhesive (LC/Duro-Tak® 87-2287 (DT2287)) system, some of the common reasons for crystallization are given (Cui and Frank 2005). Multiple theories have been proposed for the inhibition of crystal formation by the use of polymer additives and therefore stabilization of supersaturated solution of a compound in a solvent. In a study involving the preparation of supersaturated sulfamethiazole solution in presence of PVP, it was suggested that PVP formed a netlike structure over a growing crystal face with fingerlike crystal growths occurring between the pores of the PVP network, and due to the curvature of these protrusions, a higher degree of supersaturation was required to continue crystal growth (Simonelli et al. 1970). In another study involving the investigation of crystallization and morphology of hydrocortisone acetate crystal formation, it was proposed and observed via IR spectroscopy that crystal growth was inhibited by absorption of polymer, PVP into the growing crystal surface through hydrogen bonding (Raghavan et al.

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