Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain

Abstract

BackgroundThe fatty acid amide palmitoylethanolamide (PEA) has been studied extensively for its anti-inflammatory and neuroprotective actions. The lipidic nature and large particle size of PEA in the native state may limit its solubility and bioavailability when given orally, however. Micronized formulations of a drug enhance its rate of dissolution and reduce variability of absorption when orally administered. The present study was thus designed to evaluate the oral anti-inflammatory efficacy of micronized/ultramicronized versus nonmicronized PEA formulations.MethodsMicronized/ultramicronized PEA was produced by the air-jet milling technique, and the various PEA preparations were subjected to physicochemical characterization to determine particle size distribution and purity. Each PEA formulation was then assessed for its anti-inflammatory effects when given orally in the carrageenan-induced rat paw model of inflammation, a well-established paradigm of edema formation and thermal hyperalgesia.ResultsIntraplantar injection of carrageenan into the right hind paw led to a marked accumulation of infiltrating inflammatory cells and increased myeloperoxidase activity. Both parameters were significantly decreased by orally given micronized PEA (PEA-m; 10 mg/kg) or ultramicronized PEA (PEA-um; 10 mg/kg), but not nonmicronized PeaPure (10 mg/kg). Further, carrageenan-induced paw edema and thermal hyperalgesia were markedly and significantly reduced by oral treatment with micronized PEA-m and ultramicronized PEA-um at each time point compared to nonmicronized PeaPure. However, when given by the intraperitoneal route, all PEA formulations proved effective.ConclusionsThese findings illustrate the superior anti-inflammatory action exerted by orally administered, micronized PEA-m and ultramicronized PEA-um, versus that of nonmicronized PeaPure, in the rat paw carrageenan model of inflammatory pain.

N-Palmitoylethanolamine and Neuroinflammation: a Novel Therapeutic Strategy of Resolution

“…1). However, all PEA formulations showed comparable pharmacological efficacy when administered parenterally in this study [50]. These results highlight the benefit of micronization/ ultramicronization when giving PEA by the oral route.…”

“…Micronized PEA-m® and ultramicronized PEA-um® significantly improved the score in comparison to naïve PEA (PeaPure®). Intraperitoneal administration did not show a significant difference between treatment groups [50]. See [50] frequently applied in the pharmaceutical field for dissolution enhancement of poorly water-soluble drugs.…”

“…Intraperitoneal administration did not show a significant difference between treatment groups [50]. See [50] frequently applied in the pharmaceutical field for dissolution enhancement of poorly water-soluble drugs. Using this technique, microparticles are produced by reducing large drug crystals down to the micron (<10 μm) range [45][46][47].…”

“…Moreover, the rate of absorption of small drug particles is not influenced by the hydrodynamics in the gastrointestinal tract-an important factor in reducing variability of drug absorption when orally administered [49]. Using the air-jet milling technique to produce micronized and ultramicronized PEA, Impellizzeri et al [50] tested these PEA formulations in carrageenan-induced inflammation in the rat paw-a classical model of edema formation and hyperalgesia [51] extensively used in the development of anti-inflammatory drugs. Micronized and ultramicronized PEA possessed superior pharmacological action against carrageenan-induced inflammatory pain, in contrast to a preparation of non-micronized PEAwhich failed to show efficacy when given orally in this model (Fig.…”

Ultramicronized palmitoylethanolamide reduces viscerovisceral hyperalgesia in a rat model of endometriosis plus ureteral calculosis

“…The ultramicronization process reduces large drug crystals down to the submicron range (0.6-6.0 mm ultramicronized PEA vs 100-700 mm naïve PEA) and also yields a different crystalline structure increasing energy content; this enhances diffusion and distribution of the orally administered compound. 36 A total of 60 rats were used for this experiment (30 treated with placebo and 30 with ultramicronized PEA); pain behaviour was recorded in all of them, while morphological parameters (number of MCs and their percentage of degranulation, vessel number in cysts) were assessed in half of the sample (15 placebo and 15 ultramicronized PEA) and biochemical parameters (Western blot analysis: chymase, VEGF, NGF, Flk-1 in cysts) were assessed in the remaining half (15 placebo and 15 ultramicronized PEA). Nerve growth factor also was assessed in the dorsal root ganglia (DRG) in 18 of the rats (9 placebo and 9 ultramicronized PEA) used for the biochemical parameter evaluation in cysts (see details below).…”