NANOSUSPENSION, A NOVEL DRUG DELIVERY SYSTEM VIA, NOSE TO BRAIN DRUG DELIVERY

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About Authors:
N.V. Sateesh Madhav, Abhijeet Ojha, Pallavi Uniyal, Dheeraj Fulara*
DIT Faculty of Pharmacy, Mussoorie Diversion Road, Dehradun 248009,
Uttarakhand, India.
*fularadheerajmpharm@yahoo.com

Abstract:
Nanosuspension drug delivery via the nose to brain is considered to be a promising  route. This route is a useful when rapid onset of action is desired with better patient compliance than the other formulations. In terms of permeability, this route is more permeable than the other routes, which in turn is more permeable than the other route. The portion of drug absorbed through this route bypasses the hepatic first-pass metabolic processes giving acceptable bioavailability. Various techniques can be used to formulate nanosuspensions. New nanosupension  technologies address many pharmaceutical and patient needs, ranging from enhanced life-cycle management to convenient dosing for paediatric, geriatric, and psychiatric patients. This review highlights the different kind of nanosuspensions dosage forms, prepration methods of nanosuspensions, stablizers and characterization techniques of nanosuspension. factors affecting the sublingual absorption.

REFERENCE ID: PHARMATUTOR-ART-2038

INTRODUCTION
Neurotrophic factors
are naturally occurring proteins that promote the development, growth and/or survival of brain cells, making them ideal candidates to halt the progression and perhaps even reverse the course of neurodegenerative diseases in ways not possible with current symptomatic therapies. For several decades, there has been great interest in using neurotrophic factors as neuroprotective or restorative agents to treat Parkinson's, Alzheimer's and other central nervous system diseases but clinical success has not yet been achieved, largely due to the vexing challenges associated with effectively delivering these proteins to target sites in the brain.(1)

Delivering proteins or gene therapy vectors to the central nervous system has been limited by the blood-brain barrier, which normally restricts nearly all but the smallest (<0.5 kDa), lipophilic substances from passing into the brain from the bloodstream after systemic administration. Methods to bypass the blood-brain barrier have often relied upon surgically invasive procedures to deliver proteins or gene therapy vectors into the cerebrospinal fluid or brain parenchyma. Non-invasive methods targeting large, hydrophilic substances to the brain and spinal cord are greatly needed, particularly for chronic conditions where it may be necessary to repeat dosing over time.(2)

The intranasal route has many advantages for clinical use (Costantino et al, 2007): non-invasiveness, ease of application/termination, avoidance of hepatic first-pass elimination, and a growing record of experience with approved formulations (e.g. nasal spray of the 3.5 KDa polypeptide hormone calcitonin has been used to treat postmenopausal osteoporosis for many years).(3)

Diagramatic presentation of Nose to brain drug delivery
Intranasal administration of radio labelled insulin-like growth factor-I bypasses the blood-brain barrier to reach the rat nervous system.(4)

Figure-A

Autoradiographs of a sagittal brain section and a transverse trigeminal nerve section showing high signal in the olfactory bulbs and trigeminal nerve.

Figure-C

Hypothetical mechanisms conveying substances from the sub mucosa (lamina propria) into the central nervous system following nasal application.

Figure-B

Schematic of olfactory (red) and trigeminal (blue) pathways for entry of macromolecules into the brain and spinal cord following nasal application.

Fig 1: Diagramatic presentation of Nose to brain drug delivery

The first reports showing intranasal administration could target potentially therapeutic levels of macromolecules, including nerve growth factor, to the brain were described over a decade ago by Frey and coworkers.  Since that time, a rapidly growing number of published studies have demonstrated a variety of peptides and proteins, including many different neurotrophic factors, bypass the blood-brain barrier to reach or have effects in the central nervous systems of mice, rats, monkeys and human beings following intranasal application.(5) Studies in rodents have shown radiolabeled NGF, insulin-like growth factor-I (IGF-I; 7.6 kDa), insulin (5.8 kDa; ) and the cytokine interferon-β1b (18.5 kDa;) are rapidly transported to the olfactory bulb, brainstem and many other brain and spinal cord areas after intranasal application; intranasal IGF-I and NGF have also been effective in rodent models of ischemic stroke  and Alzheimer's disease , respectively.(6)

Intranasal fibroblast growth factor-2 (17 kDa) has been shown to increase neurogenesis in the olfactory bulb and subventricular zone of normal adult mice and in the subventricular zone and hippocampus of rats subjected to transient focal ischemia.

In adult cynomolgus monkeys, radiolabeled interferon-β1b is transported to many different brain areas within an hour following intranasal administration. Importantly, a number of studies suggest this administration method may also be used to target the human central nervous system.  Intranasal insulin and melanocortin (960 Da) are detectable in human CSF less than 30 minutes following administration, with no elevation in serum levels.  Intranasal insulin has also been reported to improve memory in normal adults as well as memory-impaired older individuals and to improve motor development, cognitive function and spontaneous activity in a small clinical trial involving six young children with developmental delay due to 22q13 deletion syndrome.  Other clinical trials are in progress to test whether intranasal administration of an eight amino acid peptide, derived from a larger neurotrophic factor, is beneficial in patients with Alzheimer's disease, schizophrenia-related cognitive impairment and frontotemporal dementia.(7)

ADVANTAGES & DISADVANTAGES OF ROUTE

Some of the Advantages are
1)
Easy accessibility and needle free drug application without the necessity of trained personnel facilitates self medication, thus improving patient compliances compared to parenteral routes.

2) Good penetration of, especially lipophilic, low molecular weight drugs through the nasal mucosa. For instance the absolute nasal bioavailability of fentanyl is about 80%.

3) Rapid absorption and fast onset of action due to relatively large absorption surface and high vascularization. Thus the Tmax of fentanyl after nasal administration was less than or equal to 7 minute comparable to intravenous [i.v]. Nasal administration of suitable drug would therefore be effective in emergency therapy as an alternative to parenteral administration routes.(8)

4) Avoidance of the harsh environmental conditions in the gastrointestinal tract (chemical and enzymatic degradation of drugs).

5) Avoidance of hepatic first pass metabolism and thus potential for dose reduction compared to oral delivery.(9)

6) Potential for direct delivery of drug to the central nervous system via the olfactory region, thus by-passing the blood brain barrier.

7) Direct delivery of vaccine to lymphatic tissue and induction of a secretory immune response at distant mucosal site.(10)

8) Does not require any modification of the therapeutic agent being delivered.

9)  Works for a wide range of drugs. It facilitates the treatment of many neurologic and psychiatric disorders.

10) Rich vasculature and highly permeable structure of the nasal mucosa greatly enhance drug absorption.(11)

11) Problem of degradation of peptide drugs is minimized up to a certain extent.

12) Easy accessibility to blood capillaries.

Disadvantages(12)
1)
Nasal administration is primarily suitable for potent drugs since only a limited volume can be sprayed into the nasal cavity.

2) Drugs for continuous and frequent administration may be less suitable because of the risk of harmful long term effects on the nasal epithelium.(13)

3) Nasal administration has also been associated with a high variability in the amount of drug absorbed. Upper airway infections may increase the variability as may the extent of sensory irritation of the nasal mucosa, differences in the amount of liquid spray that is swallowed and not kept in the nasal cavity and differences in the spray actuation process. However, the variability in the amount absorbed after nasal administration should be comparable to that after oral administration.(14)

4) Low bioavailability-Bioavailability of polar drugs is generally low, about 10% for low molecular weight drugs and not above 1% for peptides such as calcitonin and insulin. The most important factor limiting the nasal absorption of polar drugs and especially large molecular weight polar drugs such as peptides and proteins is the low membrane permeability.(15)

5) Mucociliary clearance- The general fast clearance of the administered formulation from the nasal cavity due to the mucociliary clearance mechanism is another factor of importance for low membrane transport. This is especially the case when the drug is not absorbed rapidly enough across the nasal mucosa. (16)

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