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ragupathyrenganathan
Nanosuspension- A Novel Drug Delivery System via Nose to Brain drug delivery!
Formulation Discussion
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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)

Mechanism
The olfactory neurons connect the brain and surrounding cerebrospinal fluid (CSF) with the open air that is inhaled via the nasal cavity.This anatomical observation raised the hypothesis that drugs may have a direct access to the central nervous system following intranasal administration.(17)

Pathways for delivery
The olfactory epithelium is a gateway for substances entering the CNS and the peripheral circulation. The neural connections between the nasal mucosa and the brain provide a unique pathway for the non-invasive delivery of therapeutic agents to the CNS.(18) The olfactory neural pathway provides both an intraneuronal and extraneuronal pathway into the brain.

The intraneuronal pathway involves axonal transport and requires hours to days for drugs to reach different brain regions. While the extraneuronal pathway probably relies on bulk flow transport through perineural channels, which deliver drugs directly to the brain parenchymal tissue and/or CSF. The extraneuronal pathway allows therapeutic agents to reach the CNS within minutes.(19)

Intranasal delivery of agents to the CSF is not surprising as CSF normally drains along the olfactory axon bundles as they traverse the cribriform plate of the skull and approach the olfactory submucosa in the roof of the nasal cavity, where the CSF is then diverted into the nasal lymphatics. The transport of drugs across the nasal membrane and into the bloodstream may involve either passive diffusion of drug molecules through the pores in the nasal mucosa or some form of non-passive transport.(20)

Figure 2: Schematic representation of pathway for nose to brain delivery(21)

Drug distribution
Drug distribution in the nasal cavity is an important factor that affects the efficiency of nasal absorption. The mode of drug administration may affect this distribution, which in turn can help determine the extent of absorption of a drug. Nasal deposition of particles is related to the individual’s nasal resistance to airflow. With nasal breathing, nearly all the particles having an aerodynamic size of 10-20 mm are deposited on the nasal mucosa.(22)

The density, shape, and hygroscopicity of particles, and the pathological conditions in the nasal passage will influence the deposition of the particle, whereas the particle-size distribution will determine the site of deposition and affect the subsequent biological response in animals and humans.(23)

Drug absorption
Passage of drug through the mucus is the first step in the absorption from the nasal cavity. Uncharged as well as small particles easily pass through mucus.

However, charged as well as large particles may find it more difficult to cross. Several mechanisms have been proposed but the following two mechanisms have been considered predominantly.(24)

  • The first mechanism of drug absorption involves an aqueous route of transport (Paracellular route). Paracellular route is slow and passive. In above route there is an inverse log-log correlation between the molecular weight of water-soluble compounds and intranasal absorption.(25) Drugs with a molecular weight greater than 1000 Daltons shows poor bioavailability.
  • The second mechanism includes transport of drug through a lipoidal route (transcellular process). Transcellular route is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity.(26) Cell membranes may be crossed by drugs by an active transport route viacarrier mediated means or transport through the opening of tight junctions.(27)

FACTORS AFFECTING NASAL DRUG ABSORPTION
The factors affecting permeability of drug through the nasal mucosa can broadly be classified into three categories as shown in following diagram.(28)

Figure 3: various factors affecting the permeability of drugs through the nasal mucosa

FORMULATION CONSIDERATIONS

Drug Molecule

* Molecular weight and size: <1000 Da

* Solubility: Higher to get dissolved in the nasal fluid and thereby to get permeated (important for particulate drug delivery).(29)

* Compound lipophilicity: Should be high for better absorption (through transcellular route), although hydrophilic small molecular weight compounds absorb through aqueous channels.(30)

* Partition coefficient and pKa: Unionized molecules easily permeate, although ionized species also permeate through different pathways.

* Therapeutic dose: <25 mg per dose(31)

FORMULATION CHARACTERISTICS

* Drug concentration: Higher the concentration, higher the permeation (up to certain extent)(32)

* Dose volume: 0.05 – 0.15 ml per dose

* Formulation pH: 4.5 – 6.5 to avoid nasal irritation. (nasal surface pH is 7.39 and pH of nasal secretions is 5.5 – 6.5)(33)

* Osmolarity: Isotonic formulation (less irritant), higher salt concentration increases permeability but is irritant to nasal mucosa.(34)

* Viscosity: Higher the viscosity, longer the residence time of formulation. But it also hinders normal physiological functions like ciliary beating and mucociliary clearance, thus affecting permeability.(35)

STRATEGIES TO IMPROVE BIOAVAILABILITY
A wide number of formulation strategies are made available to improve the bioavailability of nasal dosage forms.The basic underlying mechanisms for bioavailability enhancement are described in the following table.(36) Any one of the approaches or combination of two or more strategies is widely used to improve the bioavailability of nasal formulations.

Table 1: Strategies to improve nasal bioavailability(37)

Strategy

Examples

1.   Nasal enzyme inhibitors

Bestatin, amastatin, boroleucine, fusidic acids and bile salts

2.   Nasal permeation enhancers

Cyclodextrins, surfactants, saponins, phospholipids

3.   Prodrug approach

Cyclic prodrugs, esters, derivatization of C and N termini

4.   Nasal mucoadhesive drug delivery

Carbopol, polycarbophil, cellulose derivatives, lecithin, chitosan

5.   Particulate drug

Microspheres, nanoparticles, liposomes

Nasal formulations
Designing of nasal formulation depends upon the therapeutic need of the particular drug molecule, duration of action and duration of therapy. Both controlled release and conventional release drug delivery are possible through nasal route.(38)

Wide range of nasal formulations has been studied so far, and these include:
1. Nasal drops
2. Nasal powders
3. Nasal sprays (solution/suspension)
4. Nasal mucoadhesive particulate delivery (micro/nanoparticles, liposomes)
5. Nasal gel
6. Nasal ointments
7. Nasal microemulsions

Liquid nasal formulations
Liquid preparations are the most widely used dosage forms for nasal administration of drugs. They are mainly based on aqueous state formulations. Their humidifying effect is convenient and useful, since many allergic and chronic diseases are often connected with crusts and drying of mucous membranes. Microbiological stability, irritation and allergic rhinitis are the major drawbacks associated with the water-based dosage forms because the required preservatives impair mucociliary function.

1. Instillation and rhinyle catheter
Catheters are used to deliver the drops to a specified region of nasal cavity easily.

2. Compressed air nebulizers
Nebulizer is a device used to administer medication in the form of a mist inhaled into the lungs. The compressed air is filling into the device, so it is called compressed air nebulizers. The common technical principal for all nebulizers, is to either use oxygen, compressed air or ultrasonic power, as means to break up medical solutions suspensions into small aerosol droplets, for direct inhalation from the mouthpiece of the device.

3. Squeezed bottle
Squeezed nasal bottles are mainly used as delivery device for decongestants. They include a smooth plastic bottle with a simple jet outlet. While pressing the plastic bottle the air inside the container is pressed out of the small nozzle, thereby atomizing a certain volume. By releasing the pressure again air is drawn inside the bottle. This procedure often results in contamination of the liquid by microorganisms and nasal secretion sucked inside.

4. Metered-dose pump sprays
Most of the pharmaceutical nasal preparations on the market containing solutions, emulsionsor suspensions are delivered by metered-dose pump sprays. Nasal sprays, or nasal mists, are used for the nasal delivery of a drug or drugs, either locally to generally alleviate cold or allergy symptoms such as nasal congestion or systemically, see nasal administration. Although delivery methods vary, most nasal sprays function by instilling a fine mist into the nostril by action of a hand-operated pump mechanism. The three main types available for local effect are: antihistamines, corticosteroids, and topical decongestants Metered- dose pump sprays include the container, the pump with the valve and the actuator.(39)

Powder dosage forms
A. Insufflators
B. Dry powder inhaler
C. Pressurized MDIs

Dry powders are less frequently used in nasal drug delivery. Major advantages of this dosage form are the lack of preservatives and the improved stability of the formulation.

Compared to solutions, the administration of powders could result in a prolonged contact with the nasal mucosa.

A. Insufflators
Insufflators are the devices to deliver the drug substance for inhalation; it can be constructed by using a straw or tube which contains the drug substance and sometimes it contains syringe also. The achieved particle size of these systems is often increased compared to the particle size of the powder particles due to insufficient de-aggregation of the particles and results in a high coefficient of variation for initial deposition areas. Many insufflator systems work with pre-dosed powder doses in capsules.

B. Dry powder inhaler
Dry powder inhalers (DPIs) are devices through which a dry powder formulation of an active drug is delivered for local or systemic effect via the pulmonary route. Dry powder inhalers are bolus drug delivery devices that contain solid drug, suspended or dissolved in a non polar volatile propellant or in dry powder inhaler that is fluidized when the patient inhales. These are commonly used to treat respiratory diseases such as asthma, bronchitis, emphysema and COPD and have also been used in the treatment of diabetes mellitus. The medication is commonly held either in a capsule for manual loading or a proprietary form from inside the inhaler. Once loaded or actuated, the operator puts the mouthpiece of the inhaler into their mouth and takes a deep inhalation, holding their breath for 5-10 seconds. There are a variety o such devices. The dose that can be delivered is typically less than a few tens of milligrams in a single breath since larger powder doses may lead to provocation of cough.

C. Pressurized MDIs
A metered-dose inhaler (MDI) is a device that delivers a specific amount of medication to the lungs, in the form of a short burst of aerosolized medicine that is inhaled by the patient.

It is the most commonly used delivery system for treating asthma, chronic obstructive pulmonary disease (COPD) and other respiratory diseases.

Propellants in MDIs typically make up more than 99 % of the delivered dose. Actuation of the device releases a single metered dose of the formulation which contains the medication either dissolved or suspended in the propellant. Breakup of the volatile propellant into droplets, followed by rapid evaporation of these droplets, results in the generation of an aerosol consisting of micrometer-sized medication particles that are then inhaled.(40)

D. Nasal Gels
Nasal gels are high-viscosity thickened solutions or suspensions. Until the recent development of precise dosing devices, there was not much interest in this system. The advantages of a nasal gel include the reduction of post-nasal drip due to high viscosity, reduction of taste impact due to reduced swallowing, reduction of anterior leakage of the formulation, reduction of irritation by using soothing/emollient excipients and target delivery to mucosa for better absorption. The deposition of the gel in the nasal cavity depends on the mode of administration, because due to its viscosity the formulation has poor spreading abilities. Without special application techniques it only occupies a narrow distribution area in the nasal cavity, where it is placed directly. Recently, the first nasal gel containing Vitamin B12 for systemic medication has entered the market.(41)

Nanoparticles may offer an improvement to nose to brain drug delivery since they are able to protect the encapsulated drug from biological and/or chemical degradation, and extracellular transport by P-gp efflux proteins. This would increase CNS availability of the drug. A high relative surface area means that these vectors will release drug faster than larger equivalents, a property desirable where acute management of pain is required. Their small diameter potentially allows nanoparticles to be transported transcellularly through olfactory neurones to the brain via the various endocytic pathways of sustentacular or neuronal cells in the olfactory membrane. Surface modification of the nanoparticles could achieve targeted CNS delivery of a number of different drugs using the same ‘platform’ delivery system which has known and well characterised biophysical properties and mechanism(s) of transit into the CNS.(42)

NANO-SUSPENSION
A Nanosuspension is a submicron colloidal dispersion of drug particles. A pharmaceutical nanosuspension is defined as very finely colloid1,Biphasic2,dispersed, solid drug particles in an aqueous vehicle , size below 1*m ,without any matrix material 3, stabilized by surfactants4 and polymers5, prepared by suitable methods for Drug Delivery6 applications, through various routes of administration like oral7 ,topical ,parenteral8 ,ocular9 and pulmonary routes (pulmanory has two references10,11.A nanosuspension not only solves the problem of poor solubility and bioavailability but also alters the pharmacokinetics of drug and that improves drug safety and efficacy.(43)

Nanosuspensions differ from nanoparticles, which arepolymeric colloidal carriers of drugs (Nanospheres and nanocapsules), and from solidlipid nanoparticles (SLN), which are lipidic carriers of drug. In case of drugs that are insoluble in both water and in organic media instead of using lipidic systems nanosuspensions are used as a formulation approach. Nanosuspension formulation approach is most suitable for the compounds with high log P value, high melting point and high dose. The use of nanotechnology to formulate poorly water soluble drugs as nanosuspension offers the opportunity to address nature of the deficiency associated with this class of drugs. Nanosuspension has been reported to enhance absorption and bioavailability it may help to reduce the dose of the conventional oral dosage forms. Therefore to maintain the therapeutics, metronidazole may be used as nanosuspension with a nanoparticle size in the nano range typically between 1-1000 nm is proposed. The present study is to design metronidazole nanosuspension (MNS) as a novel controlled dosage form that could release the drug in a controlled fashion at the site to have better therapeutic efficiency at a much lower dose. Drug particle size reduction leads to an increase in surface area and consequently in the rate of dissolution as described by the Nernst–Brunner and Levich modification of the Noyes–Whitney equation .In addition, an increase in saturation solubility is postulated by particle size reduction due to an increased dissolution pressure explained by the Ostwald–Freundlich equation.(44)

PREPARATION METHODS OF NANOSUSPENSIONS
The principle techniques used in recent years for preparing nanosuspensions can be classified into four basic methods:
(a) Homogenization
(b) Wet milling
(c) Emulsification-solvent evaporation and
(d) Precipitation or microprecipitation method.

Preparation of nanosuspensions were reported to be a more cost effective and technically more simple alternative, particularly for poorly soluble drugs and yield a physically more stable product than liposomes; conventional colloidal drug carriers . Nanosuspension engineeringprocesses currently used are preparation by precipitation, high pressure homogenization, emulsion and milling techniques.

For the nanosuspensions manufacture, there are two converse methods -‘bottom-up’ and the ‘topdown’ technologies. The bottom-up technology is an assembling method from molecules to nanosized particles, including microprecipitation, microemulsion, melt emulsification method and so on. The top-down technology is a disintegration approach from large particles, microparticles to nanoparticles, such as high-pressure homogenization and media milling method.(45)

1. Homogenization
The process can be summarized into three steps-  firstly, drug powders are dispersed in a stabilizer solution to form pre-suspension; then pre-suspension was homogenized by the high-pressure homogenizer at a low pressure for several times as a kind of premilling, and finally was homogenized at a high pressure for 10-25 cycles until the nanosuspensions with the desired size were prepared .

2. Milling
Recently, nanosuspensions can be obtained by dry milling techniques. Nanosuspensions are produced by using high-shear media mills or pearl mills. The mill consists of a milling chamber, milling shaft and a recirculation chamber. An aqueous suspension of the drug is then fed into the mill containing small grinding balls/pearls. As these balls rotate at a very high shear rate under controlled temperature, they fly through the grinding jar interior and impact against the sample on the opposite grinding jar wall. The combined forces of friction and impact produce a high degree of particle size reduction.The milling media or balls are made of ceramic-sintered aluminium oxide or zirconium oxide or highly cross-linked polystyrene resin with high abrasion resistance. Planetary ball mills (PM100 and PM200; Retsch GmbH and Co., KG, Haan, Germany) is one example of an equipment that can be used to achieve a grind size below 0.1 μm. A nanosuspension of Zn- Insulin with a mean particle size of 150 nm was prepared using the wet milling technique.(46)

3. Precipitation
Precipitation has been applied for years to prepare submicron particles within the last Decade, especially for the poorly soluble drugs. Typically, the drug is firstly dissolved in a solvent. Then this solution is mixed with a miscible antisolvent in the presence of surfactants. Rapid addition of a drug solution to the antisolvent (usually water) leads to sudden supersaturation of drug in the mixed solution, and generation of ultrafine crystalline or amorphous drug solids. This process involves two phases: nuclei formation and crystal growth. When preparing a stable suspension with the minimum particle size, a high nucleation rate but low growth rate is necessary. Both rates are dependent on temperature: the optimum temperature for nucleation might lie below that for crystal growth, which permits temperature optimization.

4. Lipid emulsion/microemulsion
Another way to produce nanosuspensions is to use an emulsion which is formed by the conventional method using a partially water miscible solvent as the dispersed phase. Nanosuspensions are obtained by just diluting the emulsion . Moreover, microemulsions as templates can produce nanosuspensions. Microemulsions are thermodynamically stable and isotropically clear dispersions of two immiscible liquids such as oil and water stabilized by an interfacial film of surfactant and co-surfactant. The drug can be either loaded into the internal phase or the preformed microemulsion can be saturated with the drug by intimate mixing. Suitable dilution of the microemulsion yields the drug nanosuspension . An example of this technique is the griseofulvin nanosuspension which is prepared by the microemulsion technique using water, butyl lactate, lecithin and the sodium salt of taurodeoxycholate. The advantages of lipid emulsions as templates for nanosuspension formation are that they easy to produce by controlling the emulsion droplet and easy for scale-up. However, the use of organic solvents affects the environment and large amounts of surfactant or stabilizer are required.(47)

STABILIZERS USED IN NANOSUSPENSIONS
Stabilizer plays an important role in the formulation of nanosuspensions. The main functions of a stabilizer are to wet the drug particles thoroughly, and to prevent Ostwald’s ripening (Rawlins 1982; Muller & Bohm 1998) and agglomeration of nanosuspensions in order to yield a physically stable formulation by providing steric or ionic barriers. The type and amount of stabilizer has a pronounced effect on the physical stability and in-vivo behaviour of nanosuspensions. Typical examples of stabilizers used in nanosuspensions are cellulosics, poloxamer, polysorbates, lecithin, polyoleate and povidones. Lecithin may be preferred in developing parenteral nanosuspensions.(48)

CHARACTERIZATION TECHNIQUES
Nanosuspensions are characterized for appearance, color, odor, assay, related impurities, particle size, zeta potential, crystalline status, dissolution studies and in

1. Mean particle size and particle size distribution
The mean particle size and the span of particle size distribution (polydispersity index, PI) are two important characteristic parameters because they affect the saturation solubility, dissolution rate, physical stability, even in-vivo behavior of nanosuspensions .It has been indicated by Mu¨ ller & Peters  that saturation solubility and dissolution velocity show considerable variation with the changing particle size of the drug. Particle size distribution determines the physiochemical behavior of the formulation, such as saturation solubility, dissolution velocity, physical stability, etc. The particle size distribution can be determined by photon correlation spectroscopy (PCS), laser diffraction (LD) and coulter counter multisizer. PCS can even be used for determining the width of the particle size distribution (polydispersity index, PI). The PI is an important parameter that governs the physical stability of nanosuspensions and should be as low as possible for the long-term stability of nanosuspensions. API value of 0.1– 0.25 indicates a fairly narrow size distribution whereas a PI value greater than 0.5 indicates a very broad distribution 31.The coulter-counter gives the absolute number of particles per volume unit for the different size classes, and it is a more efficient and appropriate technique than LD for quantifying the contamination of nanosuspensions by microparticulate drugs .

2. Surface charge (zeta potential)
Zeta potential gives certain information about the surface charge properties and further the long-term physical stability of the nanosuspensions. The zeta potential of a nanosuspension is governed by both the stabilizer and the drug itself 31.For a stable suspension stabilized only by electrostatic repulsion, a minimum zeta potential of 30 mV is required whereas in case of a combined electrostatic and steric stabilizer, a zeta potential of 20 mV would be sufficient.(49)

3. Crystalline state and particle

Morphology
The assessment of the crystalline state and particle morphology together helps in understanding the polymorphic or morphological changes that a drug might undergo when subjected to nanosizing .Nanosuspensions can undergo a change in the crystalline structure, which may be to an amorphous form or to other polymorphic forms because of high-pressure homogenization. The changes in the solid state of the drug particles as well as the extent of the amorphous fraction can be determined by X-ray diffraction analysis and supplemented by differential scanning calorimetry. In order to get an actual idea of particle morphology, scanning electron microscopy is preferred.(50)

Saturation solubility and dissolution velocity
Nanosuspensions have an important advantage over other techniques, that it can increase the dissolution velocity as well as the saturation solubility. The saturation solubility of the drug in different physiological buffers as well as at different temperatures should be assessed using methods described in the literature. The investigation of the dissolution velocity of nanosuspensions reflects the advantages that can be achieved over conventional formulations, especially when designing the sustained-release dosage forms based on nanoparticulate drugs. The assessment of saturation solubility and dissolution velocity.(54)

Properties of nanpsuspension(55)

1) Physical Long-Term
Dispersed systems show physical instability due to Ostwald ripening which is responsible for crystal growth to form microparticles. Ostwald ripening is defined as the tendency for a particle dispersion to grow in diameter over time; by a process in which the smaller particles dissolve because of their higher solubility, with subsequent crystallization onto larger particles to form microparticles. Ostwald ripening is caused due to the difference in dissolution velocity/ saturation solubility of small and large particles. In nanosuspensions all particles are of uniform size hence there is little difference between saturation solubility of drug particles. The difference in the concentration of the saturated solutions around a small and large particle leads to the diffusion of dissolved drug from the outer area of the large particles. As a result the solution around large particles is supersaturated leading to the drug crystallization and growth of the large crystals or microparticles. Ostwald ripening is totally absent in nanosuspensions due to uniform particle size, which is also responsible for long-term physical stability of nanosuspensions.(56)

2) Physical Long –terrm
Dissolution of drug is increased due to increase in the surface area of the drug particles from micrometers to the nanometer size. According to Noyes-Whitney equation (equation no.1) dissolution velocity increase due to increase in the surface area from micron size to particles of nanometer size.(57)

Dx/dt = [( D x A/ h] [Cs-X/V]

BIBLIOGRAPHY
1.L. Illum, Is nose-to-brain transport of drugs in man a reality? J. Pharm. Pharmacol. 56 (2004) 3–17.
2.R.G. Thorne, G.J. Pronk, V. Padmanabhan, W.H. Frey II, Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration, Neuroscience 127 (2004) 481–496.
3.L. Illum, Nasal drug delivery — possibilities, problems and solutions, J. Control. Release 87 (2003) 187–198.
4.G.M. Eccleston, N.E. Hudson, The use of capillary rheometer to determine the shear and extensional flow behavior of nasal spray suspensions, J. Pharm. Pharmacol. 52 (2000) 1223–1232.
5.R. J. Soane, Bioadhesive polymers as intranasal drug delivery systems for peptide and protein drugs, University of Nottingham, Thesis 1999.
6.G.M. Eccleston, M. Bakhshaee, N.E. Hudson, D.H. Richards, Rheological behavior of nasal sprays in shear and extension, Drug Dev. Ind. Pharm. 26 (2000) 975–983.
7.L. Illum, Nasal clearance in health and disease, J. Aerosol Med. 19 (2006) 92–99.
8.Adams, G.L., Boies, L.R., Hilger, P.A., 1989. Boies’s Fundamentals of Otolaryngology a Textbook
9.of Ear, Nose and Throat Diseases. Saunders, Philadelphia, pp. 177–195.
10.Almeida, A.J., Alpar, H.O., Brown, M.R.W., 1993. Immune response to nasal delivery
11.Betbeder, D., Sperandio, S., Latapie, J.P., de Nadai, J., Etienne, A., Zajac, J.M., Frances, B., 2000. Biovector ™ nanoparticles improve antinociceptive efficacy of nasal morphine. Pharm. Res. 17, 743–748. of antigenically intact tetanus toxoid associated with poly(l-lactic acid) microspheres in rats, rabbits and guinea pigs. J. Pharm. Pharmacol. 45, 198– 203.
12.Brand, G., 2006. Olfactory/trigeminal interactions in nasal chemoreception. Neurosci. Biobehav. Rev. 30, 908–917.
13.Charlton, S., Jones, N.S., Davis, S.S., Illum, L., 2007a. Distribution and clearance of bioadhesive formulations from the olfactory region in man: effect of polymer type and nasal delivery device. Eur. J. Pharm. Sci. 30, 295–302.
14.Charlton, S.,Davis, S.S., Illum, L., 2007b. Evaluation of effect of ephedrine on the transport of drugs from the nasal cavity to the systemic circulation and the central nervous system. J. Drug Target. 15, 370–377.
15.Chen, F., Zhang, Z.-R., Yuan, F., Qin, X., Wang, M., Huang, Y., 2008. In vitro and in vivo study of N-trimethyl chitosan nanoparticles for oral protein delivery. Int. J. Pharm. 349, 226–233.
16.Chou, K.-J.,Donovan, M.D.,1997. Distribution of antihistamines into the CSF following intranasal delivery. Biopharm. Drug Dispos. 18, 335–346.
17.Conner, S.D., Schmid, S.L., 2003. Regulated portals of entry into the cell. Nature 422, 37–44.
18.Costantino, H.R., Illum, L., Brandt, G., Johnson, P., Quay, S.C., 2007. Intranasal delivery: physiochemical and therapeutic aspects. Int. J. Pharm. 337, 1–24.
19.Dahlin, M., Jansson, B., Bjork, E., 2001. Levels of dopamine in blood and brain following nasal administration to rats. Eur. J. Pharm. Sci. 14, 75–80.
20.Dalpiaz, A., Gavini, E., Colombo, G., Russo, P., Bortolotti, F., Ferraro, L., Tanganelli, S., Scatturin, A.,Menegatti, E., Giunchedi, P., 2008. Brain uptake of an anti-ischemic agent by nasal administration of microparticles. J. Pharm. Sci. 97, 4889–4903.
21.De Lorenzo, A., 1960. Electron microscopy of the olfactory and gustatory pathways. Ann. Otol. Rhinol. Laryngol. 68, 410–420.
22.De Lorenzo, A., 1970. Taste and Smell in Vertebrates. J&A Churchill, London, pp. 151–176.
23.Derad, I., Willeke, K., Pietrowsky, R., Born, J., Fehm, H.L., 1998. Intranasal angiotensiniI directly influences central nervous regulation of blood pressure. Am. J. hypertens. 11, 971–977.
24.Des Rieux, A., Ragnarsson, E.G.E., Gullberg, E., Preat, V., Schneider, Y.-J., Artursson, P., 2005. Transport of nanoparticles across an in vitro model of the human follicle associated epithelium. Eur. J. Pharm. Sci. 25, 455–465.
25.Dhuria, S., Hanson, L., Frey, W.I., 2008. Intranasal drug targeting of hypocretin-1 (orexin-a) to the central nervous system. J. Pharm. Sci. (Published Online).
26.Edeling, M.A., Smith, C., Owen, D., 2006. Life of a clathrin coat: insights fromclathrin and AP structures. Nat. Rev. Mol. Cell. Biol. 7, 32–44.
27.Elder, A., Gelein, R., Silva, V., Feikert, T., Opanashuk, L., Carter, J., Potter, R., Maynard, A., Finkelstein, J., Oberdorster, G., 2006. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ. Health Perspect. 114, 1172–1178.
28.Fu, T., Burbage, C., Tagge, E.P., Brothers, T.,Willingham,M.C., Frankel, A.E., 1996. Ricin toxin contains three lectin sites which contribute to its in vivo toxicity. Int. J. Immunopharmacol. 18, 685–692.
29.Gao, X.,Wu, B., Zhang, Q., Chen, J., Zhu, J., Zhang,W., Rong, Z., Chen, H., Jiang, X., 2007a. Brain delivery of vasoactive intestinal peptide enhanced with the nanoparticles conjugated with wheat germ agglutinin following intranasal administration. J. Control. Release 121, 156–167.
30.Gao, X., Chen, J., Tao, W., Zhu, J., Zhang, Q., Chen, H., Jiang, X., 2007b. Uea Ibearing nanoparticles for brain delivery following intranasal administration. Int. J. Pharm. 340, 207–215.
31.Gao, X.L., Tao, W.X., Lu, W., Zhang, Q.Z., Zhang, Y., Jiang, X.G., Fu, S.K., 2006. Lectin-conjugated PEG–PLA nanoparticles: preparation and brain delivery after intranasal administration. Biomaterials 27, 3482–3490.
32.Gartner, L.P., Hiatt, J.L., 2000. Color Atlas of Histology. Lippincott Williams &Wilkins, Philadelphia.
33.Goppert, T.M., Muller, R.H., 2005. Polysorbate-stabilized solid lipid nanoparticles as colloidal carriers for intravenous targeting of drugs to the brain: comparison of plasma protein adsorption patterns. J. Drug Target. 13, 179–187.
34.Gumbiner, B., 1987. Structure, biochemistry, and assembly of epithelial tight junctions. Am. J. Physiol. 253, C749–C758.
35.Harush-Frenkel, O., Rozentur, E., Benita, S., Altschuler, Y., 2008. Surface charge of nanoparticles determines their endocytic and transcytotic pathway in polarized MDCK cells. Biomacromolecules 9, 435–443.
36.Huang, Y., Donovan, M.D., 1996. Microsphere transport pathways in the rabbit nasal mucosa. Int. J. Pharm. Adv. 1, 298–309.
37.Illum, L., 2000. Transport of drugs fromthe nasal cavity to the central nervous system. Eur. J. Pharm. Sci. 11, 1–18.
38.Illum, L., 2004. Is nose-to-brain transport of drugs in man a reality? J. Pharm. Pharmacol. 56, 3–17.
39.Illum, L., 2006. Nanoparticle systems for nasal delivery of drugs: a real improvement over simple systems? J. Pharm. Sci. 96, 473–483.
40.Ishikawa, H., Isayama, Y., 1987. Evidence for sialyl glycoconjugates as receptors for Bordetella bronchiseptica on swine nasal mucosa. Infect. Immun. 55, 1607–1609.
41.Jogani, V.V., Shah, P.J., Mishra, P.,Mishra,A.K., Misra,A.R., 2008. Intranasal mucoadhesive
42.microemulsion of tacrine to improve brain targeting. Alzheimer Dis. Assoc. Disord. 22, 116–124.
43.Dubey R. Pure drug nanosuspensions-Impact of nanosuspension technology on  drug discovery and development. Drug Del Tech 2006; 6:65-71.
44.Shobha Rani,R.Hiremath and Hota A. Nanoparticles as drug delivery systems. Ind.J.Pharm.Sci.1999; 61(2): 69-75.
45.Mehnertw, Mader K. Solid lipid nanoparticles: Production, characterization and  applications. Adv.Drug Deliv. Rev. 2000; 47(2-3): 165-96.
46. R.H.Muller, B.H.L.Bohm and .J.Grau. Nanosuspensions : a formulation approach  for poorly soluble and poorly bioavailable drugs. In D.Wise (Ed) Handbook of pharmaceutical controlled release technology.2000; 345-357.
47. Chowdary K.P.R. and Madhavi B.L.R.,Novel drug delivery technologies for  insoluble drugs. Ind.Drugs.2005; 42(9): 557-563.
48. Cornelia M. Keck,, Rainer H. Muller.Drug nanocrystals of poorly soluble drugs  produced by high-pressure homogenisation. Eur. J. Pharm.Biopharm.2006; 62:  3–16.
49. V.B.Patravale, Abhijit A.Date and R.M.Kulkarni. Nanosuspensions: a promising  drug delivery strategy. J.Pharm.Pharcol.2004; 56: 827-840.
50. Moller RH, Grau MJ, Hildebrand GE. Increase of solubility of poorly soluble  drugs by transfer to Dissocubes using high pressure homogenization. Proc Int Symp    Control Rel Bioact Mater 1999; 26: 112-3. 18. K.P. Krause, O. Kayser, K. Mader, . nanosuspensions produced by highpressure homogenisation. Int J. Pharm.2000;  196:169–172.         52.K.P.Krause, R.H.Muller.Production and characterization of highly concentrated nanosuspensions by high pressure homogenisation. Int.J.Pharm.2001; 214:21-
51. Jan Moschwitzer,Georgr Achleitner, Herberk Pomper, Rainer H.Muller.     Development of an intraveneously injectable chemically stable aqueous  omeprazole formulation using nanosuspension. Eur. J. Pharm. Biopharm.2004;
52. Radtke M. Nanopure: Poure drug nanoparticles for the formulation of poorly soluble drugs. New Drugs 2001; 3: 62-8.
53. Dearns R. Atovaquone pharmaceutical compositions. US Patent US 6018080,  2000.
54. Sucker H. Hydrosole, eine Alternative for die parenterale Anwendung von  schwer wasserloslichen Wirkstoffen. In: Muller RH, Hildebrand GE, editors.  Pharmazeutische Technologie; Modern Arzneiformen. 2 nd ed. Stuttgart: WVG;
55.Young TJ, Mawson S, Johnston KP, Henriska IB, Pace GW, Mishra AK.Rapid expansion from supercritical to aqueous solution to produce submicron  suspensionof water insoluble drugs. Biotechnol Prog 2000;16: 402-7.
56.Shah T, Patel D, Hirani J, Amin AF. Nanosuspensions as a drug delivery  Systems -A comprehensice review. Drug Del Tech 2007;7: 42-53.
57.V.B.Patravale, Abhijit A.Date and R.M.Kulkarni. Nanosuspensions: a promisin drug delivery strategy. J.Pharm.Pharcol.2004; 56: 827-840



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