Poloxamer 407 as a solubilising agent for tolfenamic acid and as a base for a gel formulation.
A solubility phase study was carried out to investigate the ability of Poloxamer 407 (P407) to solubilise tolfenamic acid. P407 considerably enhanced the solubility of this anti-inflammatory agent, by increasing its concentration in aqueous solution at least 2000-fold (up to C=4mM), when present at 12% (w/w) at 25 degrees C. The solubilisation process was spontaneous and exothermic, as indicated by thermodynamic parameters. A mixture experimental design was used to investigate the physical and release properties of P407-based gel formulations. The experimental design allowed verifying that drug release, occurring through a Fickian diffusion mechanism, was independent of the bulk viscosity of the system. The sustained release of tolfenamic acid towards the receptor phase constituted by isopropyl myristate was accompanied, in its early stage, by the concomitant release of ethanol and tetrahydrofurfuryl alcohol (THFA) used as cosolvents to obtain a drug loading of 0.6% (w/w). The poloxamer micellar phase was directly involved in the late stage of drug release, thus indicating that a strong interaction occurred in the gel between the poloxamer and tolfenamic acid. Results point out the possibility of both the systemic and topical administration of tolfenamic acid by means of aqueous solutions or gels containing P407 at an adequate concentration.
Cafaggi
S
S
Dipartimento di Chimica e Tecnologie Farmaceutiche ed Alimentari, via Brigata Salerno 13, 16147 Genova, Italy. cafaggi@dictfa.unige.it
Russo
E
E
Caviglioli
G
G
Parodi
B
B
Stefani
R
R
Sillo
G
G
Leardi
R
R
Bignardi
G
G
D000465:Algorithms; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D005782:Gels; D016014:Linear Models; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009226:Myristates / Q000737:chemistry; D020442:Poloxamer / Q000737:chemistry*; D012044:Regression Analysis; D012995:Solubility; D012997:Solvents; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D013501:Surface-Active Agents / Q000737:chemistry*; D013816:Thermodynamics; D014783:Viscosity; D062367:ortho-Aminobenzoates / Q000008:administration & dosage* / Q000737:chemistry*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005782:Gels; D009226:Myristates; D012997:Solvents; D013501:Surface-Active Agents; D062367:ortho-Aminobenzoates; C008205:isopropyl myristate; D020442:Poloxamer; C009500:tolfenamic acid