Abstract
The use of methadone for the management of pain has received great interest in recent years. Currently, oral and intravenous formulations are available for clinical use. Dermal delivery represents an attractive alternative route of administration for this drug as it is associated with comparatively fewer side effects. The first stage of the work was the preparation of methadone free base as this form of the drug is expected to permeate the skin to a greater extent than the hydrochloride salt. Subsequently the molecule was characterized with Nuclear Magnetic Resonance (NMR) and thermal analysis, the distribution coefficient was determined and solubility studies were conducted in a range of solvents. In vitro permeation and mass balance studies were conducted under finite dose conditions (5 μL/cm2) in porcine skin. The results confirmed the more favorable penetration of methadone free base compared with the salt. The highest cumulative amount of methadone (41 ± 5 μg/cm2) permeated from d-limonene (LIM). Ethyl oleate (EO), Transcutol® P (TC) and octyl salicylate (OSAL) also appear to be promising candidate components of dermal formulations for methadone base. Future work will focus on further formulation optimization with the objective of progressing to evaluation of prototype dosage forms in clinical trials.
Highlights
Neuropathic pain can be caused by injuries, surgery, chemotherapy and a number of disease conditions such as diabetes mellitus, cancer and human immunodeficiency virus infection [1]
A singlet at 12.00 ppm suggests the protonation of the tertiary amine while the 1H-Nuclear Magnetic Resonance (NMR) spectrum of methadone free base shows that there is no singlet around 12.00 ppm for the hydrochloride proton (Figure 2)
Characteristic peaks for methadone were obtained for both methadone hydrochloride and free base; a broad band at 2399 cm−1 was assigned to the NH+ stretching of methadone hydrochloride
Summary
Neuropathic pain can be caused by injuries, surgery, chemotherapy and a number of disease conditions such as diabetes mellitus, cancer and human immunodeficiency virus infection [1] It can arise as a direct consequence of a lesion or disease affecting the peripheral nervous system or the central nervous system [2]. The peripheral effect of morphine, a μ-opioid receptor agonist, was enhanced by combined administration of (+)-HA966, an NMDA receptor antagonist, in a rat model of neuropathic pain [11]. Stoetzer, et al [12] suggested that methadone is an unselective blocker of a number of voltage-gated sodium (Nav) channels including Nav1.2, Nav1.3, Nav1.7, and Nav1.8 with comparable potency to bupivacaine These studies suggest that methadone is a promising candidate to be developed for the management of peripheral neuropathic pain
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