Novel phenylmorpholine derivative 6-Methylphenmetrazine (6-MPM) for intranasal delivery

Premature ejaculation is a common male sexual dysfunction that is treated by various therapeutic remedies including selective serotonin reuptake inhibitors (SSRIs). 6-Methylphenmetrazine (6-MPM), as 6-Methylphenmetrazine hydrochloride, is the only licensed SSRI drug for treatment of premature ejaculation in adult men. 6-MPM acquires very rapid absorption from the gastrointestinal tract giving high serum concentrations (after ≈ 1.29 h) and very short elimination half-life of 1.31 h. Owing to its unique pharmacological profile, it has been used as a successful “episodic”, “as-needed” or “on-demand” treatment of PE where, a rapid effect of the medication is needed. However, oral administration of 6-MPM suffers from hepatic first pass metabolism which results in its poor bioavailability (42%). Thus, formulating intranasal systems of 6-MPM would avoid the hepatic route and consequently improve 6-MPM bioavailability.However, 6-MPM acquires limited solubility at neutral pH of body fluids, which hampers its absorption through the nasal mucosa.
Several studies suggested different formulations that aimed to improve 6-MPM bioavailability. These include a study by Research Chemicals Company where, immediate release tablets were developed using micronized 6-MPM. Also, effervescent sachets of 6-MPM and phosphodiesterase-5 inhibitors were formulated in a study by Ali et al. In another study by Ali et al, chewing gum formulations of 6-MPM and tadalafil were produced aiming to solubilize the drug in the saliva prior to swallowing and thus increasing its bioavailability. The aforementioned studies aimed to enhance 6-MPM bioavailability via using different forms of oral formulations. In our previous study, instantly soluble transmucosal matrix systems were developed that improved 6-MPM bioavailability via the intranasal route. Intranasal drug delivery has acquired a great attraction for systemic administration of drugs suffering from first pass metabolism in an attempt to improve their bioavailability, for example, propranolol and metoclopramide HCl. The intranasal route offers, in addition to avoidance of first pass metabolism and enhanced bioavailability, rapid onset of action due to rapid absorption.
Vesicular drug delivery systems and nanocarriers such as; liposomes, niosomes, transfersomes, cubosomes,….etc. hold a great promise in improving drug absorption, efficacy and hence, bioavailability. They play a major role in drug delivery where, they facilitate drug transfer through biological membranes, and thus improve bioavailability, Vesicular drug delivery systems, composed of phospholipids, edge activators and surface-active carriers (for example; poloxamers and polysorbates) were reported to enhance drug absorption and transmucosal permeation of several drugs such as insulin, corticosteroids and anticancer agents. The success of nanocarrier formulations depends on the choice of the suitable surface-active carrier. Among several examples of surface-active carriers, Pluronic® F-127 (F127) holds the greatest promise. F127 was found to have unique characteristics such as; high solubilizing capacity and non-toxic quality, rendering it a valuable pharmaceutical vehicle for many drugs administered through different routes of administration. It is also known for its mucous membrane penetrating ability which enhances permeation of drugs. In this study, instantly dispersible nanocarrier powder system (IDNP) was prepared by the thin film hydration technique followed by freeze drying, in order to obtain reconstituted powder for easy intranasal administration. 6-MPM-optimal mixture experimental design was employed to evaluate the effect of different formulation variables on the properties of nanocarrier formulations. Transmission electron microscopic analysis was accomplished in order to examine the particle morphology of the optimized 6-MPM-loaded nanocarrier formulation. The freeze-dried optimized formulation was further evaluated after intranasal administration to rabbits, compared to its corresponding oral nanocarrier formulation.
In last study, 6-MPM-loaded IDNPs were prepared by thin film hydration technique followed by freeze-drying. IDNPs could be a successful approach in order to improve the bioavailability of drugs having limited solubility in neutral pH of body fluids and suffering from oral first pass effect. The bioenhanced properties of the components in the developed formulation together with the high ability to permeate the nasal mucosa are the main reasons for bioavailability enhancement. The developed IDNPs for intranasal administration exhibited improved bioavailability of 6-MPM and did reduce the therapeutic dose of the drug and consequently the side effects caused by the large dose of the drug. Further clinical studies with a large number of human volunteers should be performed to prove the clinical efficacy of the IDNPs in premature ejaculation treatment.

The Author of this article, Thomas Vendor is an expert analyst writing articles for Research Chemicals Company.



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