Nose to brain delivery of mirtazapine via lipid nanocapsules: Preparation, statistical optimization, radiolabeling, in vivo biodistribution and pharmacokinetic study.

Mirtazapine (MZPc) is an antidepressant drug which is approved by the FDA. It has low bioavailability, which is only 50%, in spite of its rapid absorption when orally administered owing to high first-pass metabolism. This study was oriented towards delivering intranasal (IN) mirtazapine by a direct route to the brain by means of preparing lipid nanocapsules (LNCs) as a targeted drug delivery system. MZP-LNCs were constructed by solvent-free phase inversion temperature technique applying D-Optimal mixture design to study the impact of 3 formulation variables on the characterization of the formulated nanocapsules. Independent variables were percentage of Labrafac oil, percentage of Solutol and percentage of water. Dependent variables were particle size, polydispersity index (PDI), Zeta potential and solubilization capacity. Nanocapsules of the optimized formula loaded with MZP were of spherical shape as confirmed by transmission electron microscopy with particle diameter of 20.59 nm, zeta potential of - 5.71, PDI of 0.223 and solubilization capacity of 7.21 mg/g. The in vivo pharmacokinetic behavior of intranasal MZP-LNCs in brain and blood was correlated to MZP solution after intravenous (IV) and intranasal administration in mice. In vivo biodistribution of the drug in mice was assessed by a radiolabeling technique using radioiodinated mirtazapine (131I-MZP). Results showed that intranasal MZP-LNCs were able to deliver higher amount of MZP to the brain with less drug levels in blood when compared to the MZP solution after IV and IN administration. Moreover, the percentage of drug targeting efficiency (%DTE) of the optimized MZP-LNCs was 332.2 which indicated more effective brain targeting by the intranasal route. It also had a direct transport percentage (%DTP) of 90.68 that revealed a paramount contribution of the nose to brain pathway in the drug delivery to the brain.

Mirtazapine loaded polymeric micelles for rapid release tablet: A novel formulation-In vitro and in vivo studies.

Major depression is a prevalent disorder characterized by sadness, lack of interest or pleasure, interrupted sleep or food, and impaired concentration. Mirtazapine (MTZ), a tetracyclic antidepressant drug, is commonly used to treat moderate to severe depression. MTZ is classified as a BCS class II drug that has shown bioavailability of 50% due to extensive first-pass metabolism. The aim of this research is to develop a delivery platform with enhanced solubility and oral bioavailability of MTZ through formulating polymeric micelles modeled in a rapid release tablet. Mirtazapine loaded polymeric micelles (MTZ-PMs) were formulated to enhance the solubility. Solutol® HS 15 and Brij 58 were used as combined surfactants in a ratio of (20:1) to MTZ in addition to Transcutol® P as a penetration enhancer. The following in vitro tests were performed: particle size, PDI, zeta potential, solubility factor, stability index, and transmission electron microscopes. Afterward, MTZ-PMs were converted to dry free flowable powder through loading on the adsorptive surface of Aerosil 200; then, the powder mixture was directly compressed (MTZ-PMs-RRT) into 13 mm tablets. MTZ-PMs-RRT was further investigated using in vitro evaluation tests of the tablets, namely, weight variation, thickness, diameter, hardness, friability, disintegration time, drug content, and in vitro dissolution test, which complied with the pharmacopeial limits. The pharmacokinetic parameters of MTZ-PMs-RRT compared to Remeron® tablet were further investigated in rabbits. The results showed enhanced solubility of MTZ with improved percentage relative bioavailability to 153%. The formulation of MTZ in the form of MTZ-PMs-RRT successfully improved the solubility, stability, and bioavailability of MTZ using a simple and scalable manufacturing process.

Other Antidepressants.

This chapter addresses the following FDA-approved medications for the treatment of major depressive disorder available for use in the United States including bupropion, mirtazapine, trazodone, vortioxetine, and vilazodone. These medications do not belong to one of the previously featured classes of antidepressants discussed in the preceding chapters. Each medication featured in this chapter has a unique structure and properties that target diverse receptors in the central nervous system. These diverse targets are distinct from other classes of medications used to treat major depressive disorder. This chapter will provide an overview of each medication's indication for use, history of development, pharmacology, metabolism, dosing recommendations, onset of action, use in special populations, safety and tolerability, adverse effects, potential interactions with additional medications, and data regarding possible overdose with available treatments.Bupropion was initially developed for its combined effects on the norepinephrine and dopamine neurotransmitters. Currently, bupropion is the only antidepressant on the market in the United States with no appreciable activity on serotonin concentrations in the central nervous system. Bupropion is extensively metabolized in humans into three active metabolites including hydroxybupropion, threohydrobupropion, and erythrohydrobuproprion each with substantial antidepressant activity. The most serious side effect of bupropion is the development of seizures, so the dose must be gradually titrated to a maximum dose of 450 mg per day of the immediate-release formulation and 400 mg per day of the sustained-release formulation. Additional adverse effects include agitation, dry mouth, insomnia, headaches, migraines, nausea, vomiting, constipation, and tremor. The onset of action of bupropion is 2 weeks with full efficacy attained at 4 weeks of treatment. Bupropion produced similar depression remission rates when compared to SSRIs with a median time to relapse of 44 weeks. Bupropion has additionally been approved for smoking cessation and may have a combined role in treating nicotine cravings and depression.Mirtazapine has a unique method of action by enhancing norepinephrine and serotonin neurotransmission by blocking the alpha-2 presynaptic adrenoceptors resulting in increased release of serotonin at the nerve terminals. Mirtazapine additionally binds to the 5-HT2, 5-HT3, and H1 receptors resulting in increased sedation, which is the most common side effect. Additional side effects include increased appetite and weight gain, dizziness, and transient elevations in cholesterol levels and liver function tests. Mirtazapine is unlike any other antidepressant in that it also has a hormonal effect that reduces cortisol levels within the body. Patients on mirtazapine showed significant improvement in symptoms of major depressive disorder within the first 1-2 weeks of treatment with long-term studies at 40 weeks showing continued improvements in response rates in addition to lower relapse rates. Mirtazapine has an antagonistic effect at the central presynaptic 5-HT2 receptors and alpha-2 adrenergic inhibitory autoreceptors and heteroreceptors resulting in increased norepinephrine release with an indirect release of serotonin due to increased noradrenergic input to the raphe nucleus. Mirtazapine has an effective dose range from 15 to 45 mg once daily with a long half-life preventing dose adjustments more often than every 1-2 weeks.Trazadone is a 5-HT2A and 5-HT2C receptor antagonist and selective serotonin reuptake inhibitor. While trazodone has only been FDA approved for use in the treatment of major depressive disorder, it has been used off label for numerous conditions including insomnia, anxiety, dementia, Alzheimer's disease, substance abuse, schizophrenia, bulimia, and fibromyalgia. The most common adverse reaction is drowsiness, followed by dizziness, dry mouth, and nervousness. In the United States, trazadone is the second most commonly prescribed agent used to treat insomnia. The hypnotic action of this medication at lower doses is attributed primarily to the antagonism of the 5-HT2A receptors, H1 receptors, and alpha-1 adrenergic receptors. The most active metabolite is m-chlorophenylpiperazine produced by the CYP3A4 enzyme, which is a more profound inhibitor of serotonin reuptake as compared to the parent molecule of trazadone. The maximum outpatient dose should not exceed 400 mg per day in divided doses, but in hospitalized patients, the dose may be increased to a maximum dose of 600 mg daily in divided doses while the patient is being actively monitored for side effects. One third of inpatients and one half of outpatients had a significant therapeutic response to trazadone by the end of the first week with the remainder of patients responding in 2-4 weeks of therapy.Vortioxetine is a novel antidepressant classified by the World Health Organization as a N06AX antidepressant that was derived from studies targeting the combination of direct serotonin transporter inhibition and 5-HT1A receptor modulation leading to rapid desensitization of the somatodendritic 5-HT1A autoreceptors and activation of the postsynaptic 5-HT1A receptors. This medication is an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors, an agonist at 5-HT1A receptors, and a partial agonist at 5-HT1B receptors. Blockade of the 5-HT3 receptor was noted to produce increased levels of serotonin, dopamine, norepinephrine, acetylcholine, and histamine in the prefrontal cortex and hippocampus, which are known to be associated with the development of depression. The most common adverse effect is nausea followed by sexual dysfunction, constipation, and vomiting. The maximum dose of vortioxetine is 20 mg daily with improvement in symptoms of depression noted at 2 weeks with a full therapeutic effect observed at 4-6 weeks.Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist. This medication works by enhancing serotonergic activity in the central nervous system through selective inhibition of serotonin reuptake with no significant effects noted on norepinephrine or dopamine uptake. Vilazodone additionally binds with high affinity to the 5-HT1A receptors as a partial agonist resulting in faster onset of action, greater efficacy, and better tolerability with reduced sexual side effects when compared to other SSRIs. The most common adverse effects were diarrhea, nausea, vomiting, and insomnia. Additional reported adverse effects included dizziness, dry mouth, fatigue, abnormal dreams, decreased libido, arthralgias, and palpitations which were self-limited with resolution in 4-5 days after starting the medication. The recommended therapeutic dose of vilazodone is 40 mg daily with improvement noted in depressive symptoms within 1 week of initiating therapy with increased remission rates noted at 6 weeks of therapy.The medications featured in this chapter do not fall within the major categories of antidepressant classes but add additional unique mechanisms for the treatment of major depressive disorder. Each medication targets different receptors in the central nervous system involved in the development of depression. Resolution of depressive symptoms and response rates of these medications are similar to SSRIs with reduced side effects that can often lead to discontinuation of therapy. Use of these unique medications allows clinicians to target specific symptoms and comorbidities often associated with depression resulting in improved symptom resolution and long-term maintenance of remission.

Use of thermal and non thermal techniques for assessing compatibility between mirtazapine and solid lipids.

The present investigation was aimed at the evaluation of possible interactions between mirtazapine and selected solid lipids that are commonly used to develop solid lipid nanoparticles (SLNs) and nanostructured lipidic carriers (NLCs). The solids lipids explored were palmitic acid, stearic acid, glycerylmonostearate, cutina CPPH, sterotex NF, gelucire 50/13, hydrogenated castor oil and compritol 888 ATO. The techniques used were Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR), Hot Stage Microscopy (HSM) and Isothermal Stress Testing (IST) studies. In some cases, the DSC results indicated the possibility of drug-solid lipid interactions which was further ruled out by performing HSM studies. Moreover, IST studies were also used to further confirm the compatibility between the drug and selected solid lipids. And the findings from these studies indicated compatibility between mirtazapine and solid lipids that can further be used to develop SLNs or NLCs.