Brain targeted drug delivery through nasal route

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BRAIN TARGETED DRUG DELIVERY THROUGH NASAL ROUTE GUIDED BY: DR. DHAIVAT PARIKH PHARMACEUTICAL TECHNOLOGY & BIOPHARMACEUTICS PREPARED BY: ISHANI PANDIT (14MPH109) PHARMACEUTICAL TECHNOLOGY & BIOPHARMACEUTICS 3/1/2015 1

Transcript of Brain targeted drug delivery through nasal route

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BRAIN TARGETED DRUG DELIVERY THROUGH NASAL ROUTE

GUIDED BY:

DR. DHAIVAT PARIKH

PHARMACEUTICAL TECHNOLOGY & BIOPHARMACEUTICS

PREPARED BY:

ISHANI PANDIT (14MPH109)

PHARMACEUTICAL TECHNOLOGY & BIOPHARMACEUTICS3/1/2015 1

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CONTENT

Introduction

Rational for nose to brain delivery

Anatomy of nose

Barriers for nasal delivery

Mechanism of Drug absorption

Blood supply to nasal cavity

Crucial factors for nasal formulation

Advantages & Disadvantages

Applications

Nasal drug products for systemic drug delivery in market

Conclusion 3/1/2015 2

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INTRODUCTION

Drug delivery through nasal route has been potentially explored as an alternative route for the administration of vaccines and biomolecules such as proteins, peptides and non-peptide drugs that are susceptible to enzymatic or acidic degradation and first-pass hepatic metabolism.

The nasal mucosa is one of the most permeable and highly vascularized site for drug administration ensuring rapid absorption and onset of therapeutic action.

In addition it minimizes the lag time associated with oral drug delivery and offers noninvasiveness, self medication, patient comfort and patient compliance which are hurdled in intravenous drug therapy.

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RATIONALE OF NOSE TO BRAIN DELIVERY

Currently, Nasal drug delivery has been recognized as a very promising route for delivery of therapeutic compounds including biopharmaceuticals.

Nasal administration is a logical choice for topical nasal treatments such as antihistamines and corticosteroids. The nasal mucosa has also received attention as a viable means of systemic administration of analgesics, sedatives, hormones, cardiovascular drugs, and vaccines.

Conventionally, the nasal route has been used for local delivery of drugs for treating nasal allergy, nasal congestion, or nasal infections.

However systemic delivery through the nasal route has recently begun to explore possibilities for those requiring a rapid onset of action or necessitating avoidance of severe proteolysis involved in oral administration (e.g., most peptide and protein drugs).

Successful attempts to deliver corticosteroid hormones through the nasal route for systemic absorption3 have triggered further studies in this area. 3/1/2015 4

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ANATOMY & PHYSIOLOGY OF NASAL CAVITY

The human nose is divided by the median septum, a central partition of bone and cartilage; each symmetrical half opens at the face via the nostrils and connects with the mouth at the nasopharynx. The nasal vestibule, the respiratory region and the olfactory region are the three main regions of the nasal cavity.

The lateral walls of the The sub mucosal zone of the nasal passage is extremely vascular and this network of veins drains blood from the nasal mucosa directly to the systemic circulation, thus avoiding first-pass metabolism.

the nasal cavity is covered with a mucous membrane which can be divided into non-olfactory and olfactory epithelium areas. The non-olfactory area includes the nasal vestibule, which is lined with skin-like cells and respiratory region. About 15–20% of the respiratory cells are covered with a layer of long cilia, which move in a coordinated way to propel mucus towards the pharynx. 3/1/2015 5

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nasal cavity include a folded structure which enlarges the surface area in the nose to about 150 cm2.17 This folded structure includes three turbinates. The superior, the median and the inferior.

In the main nasal airway, the passages are narrow, normally only 1–3 mm wide and this narrow structure enables the nose to carry out its main functions.

During inspiration, the air comes into close contact with the nasal mucosa and particles such as dust and bacteria are trapped in the mucus. Additionally, the inhaled air is warmed and moistened as it passes over the mucosa. This conditioning of the inhaled air is facilitated by the fluid secreted by the mucosa and the high blood supply in the nasal epithelium. 17-18

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Respiratory epithelium &mucociliary clearance:

It composed of four types of cells:

Non-ciliated

Ciliated columnar cell

Basal cell

Goblet cell

This cell prevent drying of mucosa by trapping moisture. These cell facilitated active transport processes such as exchange of water & ions between cell & motility of cilia.about 15-20% of respiratory cells covered with layer of lomg cilia. Mucus present over epithelial cell causes mucociliary clearance. Mucous moves only in one direction from the anterior to posterior part of nasal cavity to the nasopharynx. Mucous secretion gives immune protection against inhaled bacteria or virus. Mucous has water holding capacity, it exhibit surface electrical activity, it also act as transport & adhesive for particulate matter towards nasopharynx.

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Olfactory region:

In human olfactory region is located on the roof of the nasal cavities, just below the cribriform plate of the Ethmoid bone, which separates the nasal cavities from the cranial cavity22. The olfactory epithelium predominantly contain three cell types: 1. Olfactory neural cells, 2. Sustenticular(supporting) cells, 3. The basal cells.

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BARRIERS FOR NASAL DELIVERY

1. 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 are the low membrane permeability.

Drugs can cross the epithelial cell membrane either by the transcellular route or vesicular transport mechanisms or by the paracellular route. Polar drugs with molecular weights below 1000 Da will generally pass the membrane using the latter route.

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Nasal absorption of such polar drugs can be greatly improved by co administration of absorption enhancing agents.

Agents generally used for transnasal absorption includes surfactants (laureth-9, sodium laurylsulfate), bile salts ,bile salt derivatives (sodium glycocholate, sodium deoxycholate, sodium taurodihydrofusidate), fatty acids,fatty acid derivatives (linoleic acid), phospholipids (lysophosphatidylcholine), various cyclodextrins and cationic compounds like chitosan and its derivatives, poly-L-arginine, poly-L- lysine.

These enhancers work by a variety of mechanisms but generally they act by altering the permeability of the epithelial cell layer by modifying the phospholipid bilayers, leaching of proteins from the membrane or even stripping off the outer layer of the mucosa

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2. Mucocilliary 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. It has been shown that for both liquid and powder formulations, which are not bioadhesive, the half life for clearance is of the order of 15 - 30 min.

The use of bioadhesive excipients in the formulations is an approach to overcome the rapid mucociliary clearance.

The clearance may also be reduced by depositing the formulation in the anterior, less ciliated part of the nasal cavity thus leading to improved absorption 3/1/2015 12

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3. Enzymatic Degradation

Another contributing, but often less considered factor to the low bioavailability of peptides and proteins across the nasal mucosa is the possibility of an enzymatic degradation of the molecule in the lumen of the nasal cavity or during passage through the epithelial barrier. These sites both contain exo-peptidases such as mono and diaminopeptidases that can cleave peptides at their N and C terminals and endo-peptidases such as serine and cysteine, which can attack internal peptide bonds.

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MECHANISM OF DRUG ABSORPTION THROUGH NOSE

The first step in the absorption of drug from the nasal cavity is passage through the mucus. Small unchanged particles easily pass through this layer. However, large or charged particles may find it more difficult to cross.

Subsequent to a drug’s passage through the mucus, there are several mechanisms for absorption through the mucosa.

These include transcellular or simple diffusion across the membrane, paracellular transport via movement between cell and transcytosis by vesicle carriers.

Obstacles to drug absorption are potential metabolism before reaching the systemic circulation and limited residence time in the cavity. Several mechanisms have been proposed but the following two mechanisms have been considered predominantly.

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The first mechanism involves an aqueous route of transport, which is also known as the paracellular route. This route is slow and passive. There is an inverse log-log correlation between intranasal absorption and the molecular weight of water-soluble compounds. Poor bio-availability was observed for drugs with a molecular weight greater than 1000 Daltons.

The second mechanism involves transport through a lipoidal route that is also known as the transcellular process and is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. Drugs also cross cell membranes by an active transport route via carrier-mediated means or transport through the opening of tight junctions.38 For example, Chitosan, a natural biopolymer opens tight junctions between epithelial cells to facilitate drug transport.

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BLOOD SUPPLY TO NASAL CAVITY

Nasal vasculature is richly supplied with blood to fulfil the basic functions of nasal cavity such as heating and humidification, olfaction, mucociliary clearance and immunological functions. Blood supply comes from the branches of both the internal and external carotid artery, including branches of the facial artery and maxillary artery.

The name arteries of nose are:

Sphenopalatine artery

Anterior Ethmoidal Artery

Facial Artery3/1/2015 16

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NOSE TO BRAIN DELIVERY

The olfactory region is a small patch of tissue containing small receptor and is located at the very top of the nasal cavity near the inner end of the upper throat.

The patch has a yellowish tinge in contrast to its surrounding pink tissue and consists of several million tiny endings of the olfactory nerve whose bundle passes through the cribiform plate and enters the fastest forward extension of brain.

Olfactory epithelium is known to be a portal of entry of the substance into the central nervous system and peripheral circulation.

The transport of the drug across the nasal membrane and into the bloodstream may involve the passive diffusion of drug through the pores in the nasal mucosa and some from non passive transport.

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CRUCIAL FACTORS FOR NASAL FORMULATIONS

Factors related to drug:

I. Lipophilicity: Absorption of drug substance through biological membrane may be dependent on hydrophilic lipophilic balance of the compound. On increasing lipophilicity, the nasal absoption of the compound normally increases. Lipophilic compounds tend to readily cross biological membranes via the transcellular route since they are able to partition into the lipid (bilayer) of the cell membrane and diffuse into and traverse the cell in the cell cytoplasm. Nasal absorption of steroids was directly correlated with lipophillicity of drug

molecules and was found to be independent of pH.

II. Partition coefficient & pKa: According to the pH partition theory, unionized form of drug are well absorbed compared with ionized form of drug and the same theory is applicable in the case of nasal drug absorption.

III. Chemical form: The chemical form of a drug is important in determining absorption.3/1/2015 20

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IV. Molecular weight: A linear inverse correlation has been reported between the absorption of drugs and molecular weight up to 300 Daltons. Absorption decreases significantly if the molecular weight is greater than 1,000 Daltons except with the use of absorption enhancers.

V. Particle size: It has been reported that particles greater than 10 µm in size are deposited in the nasal cavity. Particles that are 2 to 10µm can be retained in the lungs and particles of less than 1 µm are inhaled.

VI. Solubility & Dissolution rate: Drug solubility and dissolution rates are important biopharmaceutical factors50 in determining nasal absorption from powders and suspensions. The particles deposited in the nasal cavity need to dissolve prior to absorption. The fluid available for dissolution of drug particles in nasal cavity or mucosa is very less when compared to the gastrointestinal fluid in oral drug delivery.51 saturation solubility of drug in a given nasal physiological pH is very important parameter, which determines the rate and extent absorption of nasal dosage form

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FORMULATION FACTORS:

I. pH of formulation: Both the pH of the nasal cavity and pKa of a particular drug need to be considered

to rationalize systemic absorption. Nasal irritation is minimized when products are delivered with a pH ranging between 4.5 and 6.5. The pH of a nasal formulation is important for the following reasons:

o To avoid irritation of nasal mucosa.

o To allow the drug to be available in unionized form for absorption.

o To prevent growth of pathogenic bacteria in the nasal passage.

o To maintain functionality of excipients such as preservatives.

o To sustain normal physiological ciliary movement .3/1/2015 22

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II. Osmolarity: Drug absorption can be affected by tonicity of the formulation. Hypertonic saline solutions are

also known to inhibit or cease ciliary activity. Low pH has a similar effect on cells as hypertonic solutions.

III. Gelling agents: Retention of the nasal formulation in the nasal cavity can enhance therapeutic effect by

virtue of enhancing rate and extent of drug absorption. increasing the viscosity may provide a means of prolonging the effect of nasal formulation.

IV. Solubilizers : The aqueous solubility of a drug is always a limitation for nasal drug delivery in solution.

Conventional solvents or co-solvents such as glycols, small quantities of alcohol, Transcutol (diethylene glycol monoethyl ether), medium chain glycerides and Labrasol (saturated polyglycolyzed C8-C10 glyceride) can be used to enhance the solubility of drugs. Other options include the use of surfactants or cyclodextrins such as hydroxypropyl-beta-cyclodextrin that serve as biocompatible solubilizers and stabilizers in combination with lipophilic absorption enhancers. In such cases, impact of the solubilizers on nasal irritancy should be considered.

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V. Drug concentration, required dose, and dose volume: Drug concentration, dose and volume

of administration are three interrelated parameters that impact the performance of the nasal delivery system. . Ex vivo experiments in rats demonstrated the effect of drug concentration on nasal drug absorption.

VI. ROLE OF ABSORPTION ENHANCERS: The selection of absorption enhancers is based upon their

acceptability by regulatory agencies and their impact on nasal physiological function. Absorption enhancers may be required when a drug exhibits poor membrane permeability, large molecular size, lack of lipophilicity and susceptibility to enzymatic degradation by aminopeptidases. Generally, the absorption enhancers act via one of the following mechanisms:

o Inhibit enzyme activity

o Reduce mucus viscosity or elasticity

o Decrease mucociliary clearance

o Open tight junctions; and

o Solubilize or stabilize the drug

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PHYSIOLOGICAL FACTORS

I. Effect of deposition on absorption: Deposition of formulation in the anterior portion of the

nose provides a longer nasal residence time and better absorption. The dosage form deposited in posterior chamber of nasal cavity will be eliminated by nasal mucocilliary clearance and hence show low bioavailability. The site of deposition and deposition pattern of liquid dosage form is dependent on the delivery device, mode of administration, physicochemical properties of drug molecule.

I. Nasal blood flow: The nasal mucosal membrane is very rich in vasculature and plays a vital role

in the thermal regulation and humidification of inhaled air. Drug absorption will depend upon the vasoconstriction and vasodilatation of these blood vessels.

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IV. Effect of mucociliary clearance: It is important that the integrity of the nasal clearance

mechanism is maintained to perform normal physiological functions such as the removal of dust, allergens and bacteria. The absorption of drugs is influenced by the residence time between the drug and the epithelial tissue. The mucociliary clearance is inversely related to the residence time and therefore inversely proportional to the absorption of drugs administered.

V. Effect of enzymatic activity: Several enzymes that are present in the nasal mucosa might

affect the stability of drugs. For example, proteins and peptides are subjected to degradation by proteases and amino-peptidase at the mucosal membrane.

VI. Effect of pathological condition: Intranasal pathologies such as allergic rhinitis, infections, or

previous nasal surgery may affect the nasal mucociliary transport process and/or capacity for nasal absorption. During the common cold, the efficiency of an intranasal medication is often compromised.

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ADVANTAGE OF NASAL DRUG DELIVERY SYSTEM

Large nasal mucosal surface area for dose absorption

Rapid drug absorption via highly vascularized mucosa

Rapid onset of action

Ease of administration, noninvasive

By pass the BBB

Avoidance of the gastrointestinal tract and first pass metabolism

Improved Bioavailability

Direct transport into systemic circulation and CNS is possible

Lower dose/reduced side effects

Improved convenience and compliance

Self-administration

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DISADVANTAGES

Volume that can be delivered into nasal cavity is restricted to 25-200 μl.

Not feasible for high molecular weight more than 1k Da

Adversely affected by pathological conditions

Drug permeability may alter due to ciliary movement

Drug permeability is limited due to enzymatic inhibition

Nasal irritants drugs cannot be administered through this route

Exact mechanism is not yet clearly known

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APPLICATIONS OF NASAL DRUG DELIVERY SYSTEM

I. Delivery of Vaccines through Nasal Route:

o Delivering the vaccine to the nasal cavity itself stimulates the production of local secretory IgA antibodies as well as IgG, providing an additional first line of defence system:

o Main reasons for exploiting the nasal route for vaccine delivery.

o The nasal passages are rich in lymphoid tissue.

o Creation of both mucosal and systemic immune responses.

o Low cost, patient compliance, non-injectable and safe

o The feasibility of the nasal route for administering vaccines against plague, diphtheria tetanus, influenza, cholera, and HIV has already been tested for inducing both mucosal and systemic immune response against the carried antigen. 3/1/2015 29

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II. Nose to Brain drug delivery system :

o The success of cell based therapy for neurodegenerative disorders depend on therapeutic properties of the cell type, on the method and safety of administration, on the amount of cells delivered to the site of injury and finally on the avoidence of excessive incorporation of the therapeutic cell into other organ and system.

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In this, methodologically transplantation may raise problem not only because of grapht rejection as a result of immunological response to the transplant. The intranasal administration of mesenchyamal stem cells and glioma cells to the brain of rodent and the enhancement of cell delivery with hyaluronidase. This biological pathway of cell migration from the nasal mucosa to the brain thus provide an opportunity for development of cell delivery method for therapeutic and experimental use in treating brain tumour model.

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III. Rapid delivery of Metoclopramide Hydrochloride: It is potent anti-emetic effective in

the treatment and vomiting associated with migraine, cancer therapy, pregnancy. It is well absorb orally and shows peak plasma concentration in 1 to 2 hours after oral dose. But due to first pass metabolism of metoclopramide hydrochloride its plasma concentration and bioavailability showing variable values between 32% to 98%. In this study nasal formulation of metoclopramide hydrochloride were developed to increase the extent of absorption through bypassing of hepatic first pass metabolism and to develop alternative antiemetic therapy. Nasal bioavailability of this drug may be improved aid of absorption promoters which include anionic enhancers such as bile salt as well as new cationic enhancers such as chitosan, protamine and poly-L-arginine.The highest promoting effect was observed with the bile salt sodium, deoxycholate where about 92% of the drug was absorb in 25 min. from the rat nasal cavity and the Kapp showed more than two fold increase as compare to controlled (from 0.045 to 0.1017 min-1) 3/1/2015 32

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IV. Insulin like growth factor-I (IGF-I): Intranasal administration is a non-invasive method of

bypassing the BBB and delivers IGF-I to the brain directly from nasal cavity along the pathway that seems to be associated with the peripheral olfactory and trigeminal system.IGF-I has been proposed as a treatment for stroke. However, it does not efficiently cross the BBB. Intracerebroventricularinjection of IGF-I has been shown to offers protection against cerebral ischemic damage in rats although this invasive method may not be practical in humans. Treatment of middle cerebral artery occlusion (MCAO).treatment was initiated 10 minute after the onset of MCAO and then again 24 hrs. And 48 hrs. Later. Intranasal dosing of 75µg IGF-I(225µg total IGF-I over 48hours) significantly reduced corrected infarct volume by 60% Vs. control (P< 0.001) and hemispheric swelling by 45.6% Vs. control(P<0.05).neurologic function assessed by the postural reflex, flexor response and adhesive tape test was also improved by intranasal IGF-I as compared to control. 3/1/2015 33

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V. Intranasal Insulin delivery: The oral route is preferred for administration of drug, particularly

those required in chronic therapy, it is not feasible for the systemic delivery of most peptide and protein drugs including insulin. Due to the poor oral availability insulin is now a days administered parenterally. There are numorous disadvantages to injectable insulin therapy. The difficulties in achieving normal physiological profile of insulin by injectable therapy has led to the investigation of alternative, non-parenteral, route for the delivery of insulin in an attempt to improve glycemiccontrol. There are number of other non- parenteral route other than oral route which have been investigated for the systemic administration of peptide and protein drug such as transdermal, ocular, buccal, rectal, vaginal, pulmonary and nasal route. Out of all this route intranasal route is more viable and effective.

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Sephadex (dextran microsphere)was shown to promote nasal insulin absorption in rats, although DEAE-sephadex(DEAE- dextran microsphere)was ineffective which correlated with the in vitro release characteristic of insulin from microsphere system.dextran microsphere which were coated with insulin were shown to be more effective in terms of promoting insulin absorption in rats than insulin-loaded microsphere. By using chitosan polymer as absorption enhancer the different percentage of chitosan is used for making formulation for intranasal administration.0.5%and 1.5%chitosan was used this shows increase in bioavailability through intranasal administration of insulin.

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NASAL FORMULATIONS

The deposition and deposition area are mainly a function of the delivery system and delivery device. Different dosage forms and their application to deliver the drugs to the central nervous system following intranasal drug delivery are discussed in this section.

LIQUID DOSAGE FORMS

Liquid dosage forms either in form of soluble, suspended or colloidal systems are normally used for

formulating nasal delivery systems.

Nasal sprays: Both solution and suspension formulations can be formulated into nasal sprays. Due

to the availability of metered dose pumps and actuators, a nasal spray can deliver an exact dose anywhere from 25 to 200 µL. The particle size and morphology (for suspensions) of the drug and viscosity of the formulation determine the choice of pump and actuator assembly. Solution and suspension sprays are preferred over powder sprays because powder results in mucosal irritation.

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Nasal emulsions, microemulsions and nanoparticles: Intranasal emulsions and

nanoparticles have not been studied as extensively as other liquid nasal delivery systems. Nasal emulsions offer the advantages for local application mainly due to the viscosity. One of the major disadvantages is poor patient acceptability. The physical stability of emulsion formulations and precise delivery are some of the main formulation issues.

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SEMI-SOLID DOSAGE FORMS:

Semi-solid systems, for example gels, ointments and liquid systems containing polymers that gel at particular pH changes are usually employed for designing the nasal drug delivery systems.

Nasal gels Nasal gels are thickened solutions or suspensions, of high- viscosity. The advantages of a nasal gel include the reduction of post-nasal dripping due to its high viscosity, reduction of the 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 the mucosa for better absorption.67 Vitamin B12 and apomorphine gel have been successfully employed to achieve desired therapeutic concentrations following nasal administration.

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SOLID DOSAGE FORMS:

Solid dosage forms are also becoming popular for intranasal drug delivery, although these formulations are more suitable for pulmonary drug delivery and similar applications, since it can cover the vasculature within the epithelium of nasal mucosa.

Nasal powders: Powder dosage forms may be developed if solution and suspension dosage forms cannot be developed, mainly due to lack of drug stability. The advantages of nasal powder dosage form are the absence of preservative and superior stability of the drug in the formulation. However, the suitability of the powder formulation is dependent on the solubility, particle size, aerodynamic properties and nasal irritancy of the active drug and/or excipients. An additional advantage of this system is local application of drug, but nasal mucosa irritancy and metered dose delivery are some of the challenges for formulation scientists and device manufacturers who are interested in powder dosage forms.

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NEEDS AND FUTURE PROSPECTIVES OF NASAL DRUG DELIVERY

In the field of drug delivery, drug delivery technologies will play a key role in the success of the industry. The need for non-invasive drug delivery systems continues due to poor acceptance and compliance with the existing delivery systems. The current needs of the industry are improved solubility/stability, biological half-life and bioavailability enhancement of poorly absorbed drugs. Key issues facing the biopharma industry are to improve safety, improve efficacy for organ targeting, and improved compliance via sustained release or increasing residence time of drug at the site of application.

New technologies include improved nasal formulations; site specific release, carrier- based systems, advanced spray formulations, atomized mist technology, preservative free system and integrated formulation development are strictly needed for success of drug delivery through nasal mucosa. For success of nasal drug delivery Researchers has to on:

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Development of delivery technologies to increase efficacy and reduce side effects by target delivery with variations potential of the drug.

Development of new technologies to deliver macromolecules with utilization of biotechnology and high technology.

Development of integrated/improved nasal formulations.

Development of integrated device development for successful delivery of therapeutics.

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CONCLUSION

Drug delivery through nasal route provides a practical, non invasive method of by passing the blood brain barrier (BBB) in order to deliver therapeutic agents to the brain. This method allows drugs that do not cross the BBB to be delivered to the central nervous system in a few minutes along with both the olfactory and trigeminal neuronal pathway.

This delivery system has clinical benefits like reduction in drug dosage and systemic exposure, which results in lesser side effects. It is expected that nasal drug formulations will continue reach to the market and this delivery will include not only drugs for acute and chronic disease but also novel nasal vaccines for local or systemic protection against microbial infection. However it is well known that intranasal route has several limitations which must be overcome to develop a successful nasal formulation.

Drug related factor and pathophysiological condition of nose determine the nasal drug absorption. Some common approaches, like increasing the nasal residence time of drug, use of absorption or penetration enhancers and minimization of the mucociliary clearance, enhances the bioavailability of nasally administered drug.

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This route is believed to be an alternative route to oral and parenteral because of the successful administration of vaccines and biomolecules such as proteins, peptides and non-peptide drugs, that are susceptible to enzymatic or acidic degradation and first-pass hepatic metabolism .Moreover it also offers noninvasiveness, self medication, patient comfort and patient compliance which are hurdled in intravenous drug therapy

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REFERENCES

Arun Kumar Singh et al; “Nasal Cavity: a promising transmucosal platform for drug delivery and research approaches from nasal to brain targeting ”, Journal of Drug Delivery & Therapeutics; 2012, 2(3): 22-33.

Choudhary Rakhi et al; “Nasal route: A Novelestic Approch for Targeted Drug Delivery to CNS”, International research Journal of Pharmacy, 2013, 4(3).

Kapil Kulkarni et al; “Brain Targetting through Intranasal Route”, International Journal of PharmTechResearch, Vol.5, No.4, pp 1441-1450, Oct-Dec 2013.

Daljeet Sharma et al; “Drug Targeting to Brain : A Review”, International Journal of Pharmaceutical Research and Development, 2011/PUB/ARTI/VOV-3/ISSUE-1/MARCH/004.

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Thank You

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