An Overview of Formulation Strategies for Treatment of Depression with its Advance Devices

Introduction

Depression can be difficult to recognize and diagnose in people with intellectual disabilities (ID) because of their cognitive and verbal limitations and different manifestations of depression in this group compared to the general population.¹

Astrocytes are the most plenteous glial cells in the cerebrum. In addition to their classical roles giving physical help to neurons or the expulsion of neuronal waste, astrocytes are dynamic controllers of cerebrum which works by discharging purported “gliotransmitters, for example, Adenosine triphosphate, glutamate and D-serine. Of these, Adenosine triphosphate has gotten expanded consideration since it is discharged from astrocytes and intercedes different capacities to manage neighboring cells.²

The most frequently cited reason given for theclinical preference for Selective serotonin reuptake inhibitors (SSRIs) is not their efficacy, which is generally considered to be comparable to other common antidepressantsTricyclic antidepressant (TCAs) and monoamine oxidase inhibitors (MAOIs), but rather their superior tolerability and safety.³

The transdermal patch of long-acting shows the issue of dose depletion which is caused by extremely high permeation rate should be avoided, the permeation rate of high permeability drug must be down regulated to an appropriate level to obtain a controlled release patch⁴ .

New Formulations of Existing Antidepressants

Mirtazapine

An orally disintegrating tablet formulation of mirtazapine has been developed. Single oral doses of the marketed immediate-release formulations of mirtazapine exhibits that the drug is rapidly absorbed with peak plasma concentrations (Cmax) within 1–2 hours.⁵ Manufacturer: Aurobindo pharma ltd

Approval date: December 8, 2005

Strength(s): 15mg, 30mg.mg.

Enteric-Coated Weekly Fluoxetine

Fluoxetine is one of the selective serotonin reuptake inhibitors (SSRI) which is marketed as a racemic mixture (50/50) of its R- and S-enantiomers. An enteric-coated capsule containing 90mg of the drug is given once a week. It is designed to extend dissolution until the pellets reach a portion of the gastrointestinal tract pH exceeds 5.5.The capsules also contain other inactive ingredients: hydroxy-propyl-methyl-cellulose forms the enteric film coating material.⁶

Extended-Release Venlafaxine

Venlafaxine has a single chiral center and exists as a racemic mixture of R-(–)- and S-(+)-enantiomers. The R-enantiomer exhibits dual presynaptic inhibition of serotonin and noradrenaline reuptake, while the S-enantiomer is a serotonin reuptake inhibitor.7 A microencapsulated formulation of venlafaxine was developed as an extendedrelease capsule (venlafaxine extended release) and marketed as a once-daily dose. The t1/2for venlafaxine and O-dimethylvenlafaxine was 10.3 ± 4.4 hours and 14.6 ± 4.2 hours in the venlafaxine extended release 150mg group compared with 5.0 ± 3.2 hours and 9.6 ± 2.5 hours in the immediaterelease group.⁸

Paroxetine Controlled-Release

About 80% of the paroxetine content of the tablets is released, the remaining 20% is retained in patients treated within each tablet. The individual dose of paroxetine controlled release needs to be about 25% higher than that of an immediate-release formulation of paroxetine to achieve equivalent dosing.9 Treatment-resistant depression¹⁰ The chance of remission of symptoms reduces significantly following a failure to respond to the initial antidepressant choices.

Electroconvulsive therapy (ECT) also remains effective and recommended short-term treatment for severe or life-threatening depression.The benefits of ECT, however, are rarely prolonged and an antidepressant must also be prescribed to reduce the risk of a relapse of symptoms. Diseases associated with depression Depression is often found co-morbid with various medical illnesses such as arthritis, asthma, cancer, cardiovascular disease, diabetes, hypertension, chronic respiratory disorders and a variety of chronic pain conditions adding tremendously to the morbidity burden.

Diabetes

Diabetes has both short term and long-term obstacles as a protracted illness. The long-term diabetes maycause various demonstrative problems like depression, dysthymia and anxiety disorder. Between diabetes and depression, a bidirectional relationship is observed. It is well documented that the incidence of depression is developed in patients having Diabetes mellitus equaled to those without diabetes¹¹.

Gestational diabetes

Postpartum depressive symptoms are associated with a complex risk of Gestational diabetes. Screening for Gestational diabetes will help to identify target women at high risk of the disease and offer them the health care that may prevent adverse pregnancy outcomes such as macrosomia and cesarean. The relationship between depression and gestational diabetes mechanisms are indeterminate. The production of inflammatory cytokines and stress hormones increases the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system which were biologically activated by the immune dysfunction associated with depression.The pancreatic β-cells can associate with both inflammatory cytokines and stress hormones to prompt insulin obstruction. Moreover, physical inactivity, poor diet and other behavioral problems with many lifestyle choices that increase the risk of diabetes linked todepression.¹²

Cancer

The cancer patients have higher chance of morbidity and mortality attributable depression risk rather than depression as a risk factor for subsequent cancer. The causes of cancer are complex and are related to genetic factors, unhealthy lifestyles, environmental factors and psychological factors, including depression.¹³

Cardiovascular disease The people with depression have a 30–87% highe risk of experiencing an ischaemic heart disease (IHD).A similar outline of connotation has been designated amongst depression and stroke: depression increases the risk of incident fatal or non-fatal strokes by 29–63%¹⁴.

Children and Adolescents

A bidirectional relationship between medical illness and depression associated with the medical illness being a risk factor for depression. The Depression may increase treatment nonadherence, worsen physical disease and lead poor functioning, greater health care use and increased school absenteeism.¹⁵

Perimenopause

In some women, depression can present or worsen during periods of dynamichormonal flux such as pre menstruum, peripartum and perimenopause. Premenopause to postmenopause stages of reproductive life indicates that some women may demonstrate a greater sensitivity to gonadal steroid shifts concerning negative mood symptoms.¹⁶

Drug formulations still in research stages¹⁷

These formulations are not yet economically accessible and furthermore only a few antidepressants that can be formulatedin dierent formulations.

Intramuscular

The Psychotropic medications which are delivered by intramuscular i.m route are presently used for binary resolutions: to deliver quick tranquilization in an alternative setting and as depot antipsychotics. The salient features of the IM route are fast absorption, avoidance of first-pass metabolism, and ensured compliance. The bioavailability is often less than 100% because of drug retention and metabolism by local tissues, repeated injections of some drugs may cause local irritation or abscesses, and cautionary use in cachectic patients and those with poor muscle perfusion. Intramuscular ketamine appears to be a promising agent. There is evidence of ketamine 0.5mg/kg i.m injection rapidly alleviating depressive symptoms and suicidal ideation.¹⁸

Inhalational

The inhalation route could be a potentially beneficial route for systemically acting medication owing to the large surface area of the lungs and the good relative permeability of vasculature.¹⁹

Intranasal

The absorption over the nasal routes bypasses the gut and permits the transport of drugs into the central nervous system via the olfactory and trigeminal nerve pathways. Intranasal administration can be used to deliver doses of up to approximately 20mg.²⁰

Sublingual

The sublingual site has a rich supply of capillaries and high permeability thus promoting rapid absorption and also bypassing the first-pass metabolism. This may be an efective route, especially for non-ionized, highly lipid-soluble medications²¹.

Transdermal drug delivery system

Transdermal therapeutic systems (TTS), usually called “patches,” frequently involve three portions: an adhesive, an active pharmacologic agent and enhancing agents. An innovative patch design is a liquid reservoir system where the patch is entailed of backing material (that is both protective and adhesive), a liquid drug reservoir and a release membrane. The passive designs of either the reservoir or matrix designs, once a patch is applied to the skin a diffusion gradient is established and the drug moves into the stratum corneum (or outer layer of the skin). Transit through the stratum corneum is carried out by diffusion through intercellular lipids. This is the rate-limiting step in passive transdermal drug delivery. Therefore, medicines that are suited for passive patch technology have a small molecular mass (< 500 Da) and are lipophilic.²²

Ideal properties of transdermal drug delivery system²³

Transdermal drug delivery permits controlled release of the drug into the patient and it enables a steady blood level profile which leads to reduced systemic side effects and improved efficacy over other dosage forms. The main aim of the transdermal drug delivery system is to administer drugs into systemic circulation through the skin at a predetermined rate with minimal inter and intrapatient variation with user-friendly, convenient, painless and is multi-day dosing, it offers improved patient compliance too.^22-23

Advanced devices

To establish a plasma drug concentration at the minimum therapeutic level, the properties of skin barrier must be overcome before the active transdermal controlled delivery of drugs can be effectively accomplished. Modification of the conventional device is increasingly being attempted for achieving the goal of reducing the skin’s barrier properties and enhancing transdermal permeation of drugs.

Micro blades

The previous studies intended to scheme a device for percutaneous drug delivery by disabling the skin’s natural barrier by making use of microprojections. It was hypothesized that the need for such a device existed that once a drug penetrated through stratum corneum with the aid of the device, permeation over the enduring layers could proceed readily.²³

Microneedles

Microneedles are fitted in a gel-filled compartment that was originated to be capable of opening the skin permeation pathways up to a depth of 150 µ when applied with pressure. A sealing mechanism was also incorporated to contain the drug in one or more reservoirs until it was ready to be delivered. In addition, it included a rate control mechanism to regulate rate and extent of drug delivery and an adhesive thus, immobilizing the microneedles during its insertion into the skin.²⁴

Needleless Syringe

This device features an elongated, tubular duct having a lumen for delivering the particles towards the target tissue. The device has a membrane that is ruptured by gas pressure to create a supersonic gas flow in which the therapeutic agent is injected.²⁵

Mechanical Vibrations

For increasing the drug absorption through skin mechanical vibrations may be used. To increase the absorption of substances electrical pulses are used in conjunction with mechanical vibrations. To increase the absorption effect frequency and phase of electrical and mechanical vibrations were synchronized.²⁶

Ultrasound

To treat patients with local musculoskeletal inflammation physiotherapists used ultrasound using topically applied steroids. For the treatment of cancers (sonodynamic therapy) ultrasound was explored for chemical activation of drugs. To enhance the effects of thrombolytic agents such as urokinase,ultrasound energy was used. Previous attempts to use high-frequency ultrasound (~1 MHz and ~1-3 W/cm2) to enhance transdermal drug delivery produced inconsistent results and were found to vary significantly from drug to drug.²⁷

Electroporation

A biologically active agent can be introduced into cells by injecting it and applying an electric field to that region. This causes electroporation before,simultaneously and/or subsequently to injection of agent. In the first technique, one of the injectors was the donor electrode and the other injector was the return or counter electrode.²⁸

Iontophoresis

Iontophoresis comprises the application of electromotive force to an initiative or resists oppositely charged ions over the dermal layers into the area to be treated, either into the surrounding tissues for localized treatment or into the circulatory system for systemic treatment. Positively charged ions are driven into skin at the anode while negatively charged ions are driven into skin at the cathode.²⁹

Limitations of existing therapy

Some of existing therapy hasvarious side effects like sexual dysfunction, rage, headache, insomnia, fatigue, thirst,and gastrointestinaldisorders. These side effects could be associated with high and variable plasma drug levels caused by inter-subject variationsin CYP2D6-mediatedhepatic first-passm etabolismandoralbioavailability.³⁰

Epidemiology of depression

The epidemiology of depression has been studied across the world. Depression is a major cause of morbidity worldwide. Lifetime prevalence estimates vary widely, from 3% in Japan to 17% in the United States. Epidemiological data shows higher rates of depression in the Middle East, North Africa, South Asia and America than in other countries. A recent systematic review of the global prevalence of common mental disorders found agestandardized prevalence in East Asia (3.8% of females, 2.3% of males) and in Asia Pacific (3.2% of females, 1.9% of males) substantially below the worldwide prevalence (5.5% of females, 3.3% of males). ³¹

CONCLUSION

This review mainly focuses on a new formulation of existing antidepressant drugs which is specific to selective serotonin reuptake inhibitors, like Enteric-Coated Fluoxetine which is found to increase dissolution and decrease the frequency of drug administration, extendedRelease venlafaxine as microencapsulated formulation marketed as a once-daily dose. And review also employs the formulation still under research possessing innovative criteria than existing formulation which includes the Psychotropic medications which are delivered by i.m route are presently used for binary resolutions, Inhalation route potentially beneficial route for systemically acting medication owing to the large surface area of the lungs and the good relative permeability of vasculature. The sublingual site has a rich supply of capillaries and high permeability thus promoting rapid absorption and specific to Transdermal drug delivery which permits controlled release of the drug into the patient and it enables a steady blood level with the advanced devices that are used for the formulation of antidepressant drugs. Thedepression is related to some of diseases and which can suppress the symptoms of depression. Thereby it is concluded that recent or advanced new formulation of the existing drug can be a better choice for the therapy for depression than that of traditional formulations.