Diclofenac Salts, VIII. Effect of the Counterions on the Permeation through Porcine Membrane from Aqueous Saturated Solutions.

Adamo Fini,Annamaria Monastero,Glenda Bassini,Cristina Cavallari

doi:10.3390/pharmaceutics4030413

Abstract

The following bases: monoethylamine (EtA), diethylamine (DEtA), triethylamine (TEtA), monoethanolamine (MEA), diethanolamine (DEA), triethanolamine (TEA), pyrrolidine (Py), piperidine (Pp), morpholine (M), piperazine (Pz) and their N-2-hydroxyethyl (HE) analogs were employed to prepare 14 diclofenac salts. The salts were re-crystallized from water in order to obtain forms that are stable in the presence of water. Vertical Franz-type cells with a diffusional surface area of 9.62 cm2 were used to study the permeation of these diclofenac salts from their saturated solutions through an internal pig ear membrane. The receptor compartments of the cells contained 100 mL of phosphate buffer (pH 7.4); a saturated solution (5 mL) of each salt was placed in the donor compartment, thermostated at 37 °C. Aliquots were withdrawn at predetermined time intervals over 8 h and then immediately analyzed by HPLC. Fluxes were determined by plotting the permeated amount, normalized for the membrane surface area versus time. Permeation coefficients were obtained dividing the flux values J by the concentration of the releasing phase—that is, water solubility of each salt. Experimental results show that fluxes could be measured when diclofenac salts with aliphatic amines are released from a saturated aqueous solution. Different chemical species (acid, anion, ion pairs) contribute to permeation of the anti-inflammatory agent even though ion-pairs could be hypothesized to operate to a greater extent. Permeation coefficients were found higher when the counterion contains a ring; while hydroxy groups alone do not appear to play an important role, the ring could sustain permeation, disrupting the organized domains of the membrane.

Highlights

Transdermal delivery of drugs offers important advantages over oral administration, especially when drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), promote adverse effects in the stomach and intestine
Salt forms are often preferred in commercial formulations to obviate solubility problems, even though in the ionized or salt form the permeability of the drug could generally be greatly reduced, due to its lower partition coefficient [19]
In the case of diclofenac, salts with aliphatic amines can be partitioned towards an n-octanol phase [6], or penetrate through human skin [9,20], even in iontophoretic experiments [1], or in combination with chemical enhancers [4], or by means of special formulations [21,22,23]

Summary

Introduction

Transdermal delivery of drugs offers important advantages over oral administration, especially when drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), promote adverse effects in the stomach and intestine. This route is easy and painless, it protects the active compound from gastric enzymes, and it avoids the hepatic first-pass effect. The success of a transdermal drug delivery system depends on the ability of the drug to penetrate the skin in sufficient quantities to maintain therapeutic levels, at least locally near the site of administration. The skin, is a natural barrier, and only a few drugs can penetrate the skin and in sufficient quantities to be effective. A large percentage of drugs, which are weak acids or bases, are usually used in their un-ionized form to enhance permeability by topical forms

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