Overview AQUEOUS NASAL DOSAGE FORM

In the name of Allah and entire praise for only Almighty Allah who has given me the ability for completing my project paper and the opportunity to study in this subject.

I would like to express my profound gratitude and sincere regards to my esteemed Teacher & Supervisor, SM Ashraful Islam, Associate professor Dept. of Pharmacy, University of Asia Pacific for his unbound enthusiasm & rationalist ideas and excellent guidance.

It is my pleasures to express my gratefulness and thanks to Dr. Mohiuddin Ahmed Bhuiyan, professor & Head, Mohammad Shahriar., Assistant professor, Dept .of Pharmacy, University of Asia Pacific for kind help in several occasions for this project.


I shall also like to express my thanks to my class mates especially Almas Sultana, Nahid Newaz Riad, Hosne-Ara Lipi for their unfailing affection suggestion, encouragement & cooperation in many aspect of this project. Their valuable criticize helped me & made it possible for me to complete the work embedded in this project. A warm salute to all who were directly or indirectly interconnected during my Project work. I fell happy to announce another extroverts individuals whose contribution can never be forgotten.

At last but not least, I would express my heartfelt gratitude to my respected father & mother and my beloved sister for their great sacrifice in leading me to proper intellectual pursuit. Their immeasurable love affection & encouragement to complete the project work with confidence for my better tomorrow.

LIST OF CONTENTS
Serial No.
Name of Topic
Page No.
1.
INTRODUCTION
1-4
2.
NASAL ANATOMY AND PHYSIOLOGY INFLUENCING DRUG DELIVERY
4-11
2.1
Regulation of nasal airflow
4-5
2.2
The nasal valve and aerodynamics
5-6
2.3.
The nasal mucosa—filtration and clearance
7
2.4.
The nasal cycle
7-8
2.5.
Nasal and sinus vasculature and lymphatic system
8-9
2.6.
Innervations of the nasal mucosa
9-10
2.7.
The sensitivity of the nasal mucosa as a limiting factor
10-11
2.8.
Targeted nasal delivery
11
3.
MECHANISM OF NASAL ABSORPTION
12
3.1.
First mechanism
12
3.2.
Second mechanism
12
4.
LIQUID NASAL FORMULATION DEVICES
12-14
4.1.
Instillation and rhinyle catheter:
13
4.2.
Compressed air nebulizers
13
4.3.
Squeezed bottle:
13-14
4.4.
Metered-dose pump sprays
14
5.
FORMULATION SELECTION CONSIDERATIONS
14-22
5.1.
Preformulation and Bulk Drug Properties:
15
5.2.
Drug concentration, dose and dose volume
15
5.3.
pH of the formulation
15-16
5.4.
Buffer capacity
16
5.5.
Viscosity
16
5.6.
Formulation osmolarity
16
5.7.
Selection of Excipients
16-17
5.8.
Permeation Enhancers:
17-19
5.9.
Preservatives
19-21
5.10.
Stability and Compatibility
21
5.11.
Processing Issues
21-22
6.
DEVICE SELECTION CONSIDERATIONS
22-32
6.1.
Devices for liquid formulations
24-29
6.2.
Performance parameters
29-32
7.
REGULATORY ASPECTS
32-34
8.
NASAL DFELIVERY OF PEPTIDES AND PROTEINS
35-36
9.
CONCLUSION
37
10.
REFERENCE:
38-46



LIST OF TABLES
Serial No.
Name of Table
Page No.

Table- 1

Some marketed aqueous nasal products in the United States and United Kingdom.


2-4
Table-2
Common excipients used in aqueous nasal products.
20-21

LIST OF FIGURES
Serial No.
Name of Figure
Page No.

Figure-1

The complex anatomy of the nasal airways and paranasal sinuses.

6
Figure- 2
Illustration of the of the nasal delivery process.
6
Figure-3
Parts for a standard pump and how it looks like when assembled.
23
Figure- 4
Cross-section of a traditional nasal device.
24
Figure- 5
Nasal spray pumps.
31




















Summary of Study
Dosage forms are essentially pharmaceutical products in the form in which they are marketed for use, typically involving a mixture of active drug components and non-drug components (excipients). Depending on the method/route of administration, dosage form comes in several types. These include many kinds of solid, liquid and semi-solid preparation. Among various dosage forms nasal dosage form has occupied a significant area in the field of medicine. In recent years, many drugs have been shown to achieve better systemic bioavailability through nasal route than by oral administration. Aqueous nasal dosage forms are most widely used dosage form for nasal drug administration. They are based on aqueous state formulation. Their humidifying effect is convenient for many allergic and chronic diseases. Nasal drug delivery system is a promising route of administration for the several systemically acting drugs with poor bioavailability. This project has provided a thorough discussion on aqueous nasal dosage form which presents an overall idea about aquous nasal dosage form associated with nasal drug administration.

















1. INTRODUCTION
Each type of dosage form is unique in its physical and pharmaceutical characteristics. Based on route of administration dosage form can be classified as Oral, Parenteral, Transdermal, Rectal, Urethral, Sublingual, Intranasal, Conjunctival, Intra-ocular and Intra-respiratory. Of them Intranasal dosage forms or drug delivery system has some unique features.

Nasal spray products contain therapeutically active ingredients (drug sub- stances) dissolved or suspended in solutions or mixtures of excipients (e.g., preservatives, viscosity modifiers, emulsifiers, buffering agents) in nonpressurised dispensers that use metering spray pumps (FDA 1999).
Nasal mucosa has been considered as a potential administration route to achieve faster and higher level of drug absorption because it is permeable to more com- pounds than the gastrointestinal tract due to lack of pancreatic and gastric enzymatic activity, neutral pH of the nasal mucus and less dilution by gastrointestinal contents (Krishnamoorthy and Mitra, 1998; Jadhav et al., 2007). In recent years many drugs have been shown to achieve better systemic bioavailability through nasal route than by oral administration. Nasal therapy, has been recognized form of treatment in the Ayurvedic systems of Indian medicine, it is also called "NASAYA KARMA" (Chien et al., 1989). Nasal drug delivery - which has been practiced for thousands of years, has been given a new lease of life. It is a useful delivery method for drugs that are active in low doses and show no minimal oral bioavailability such as proteins and peptides. One of the reasons for the low degree of absorption of peptides and proteins via the nasal route is rapid movement away from the absorption site in the nasal cavity due to the mucociliary clearance mechanism.

The nasal route circumvents hepatic first pass elimination associated with the oral delivery: it is easily accessible and suitable for self-medication. During the past several decades, the feasibility of drug delivery via the nasal route has received increasing attention from pharmaceutical scientists and clinicians. Drug candidates ranging from small metal ions to large macromolecular proteins have been tested in various animal models (Chien et al., 1989). It has been do- cumented that nasal administration of certain- hor- mones and steroids have resulted in a more complete absorption (Hussain et al., 1979; Hussain et al., 1981). This indicates the potential value of the nasal route for administration of systemic medications as well as utilizing this route for local effects. For many years drugs have been administered nasally for both topical and systemic action. Topical adminis- tration includes the treatment of congestion, rhinitis, sinusitis and related allergic or chronic conditions, and has resulted in a variety of different medications including corticoids, antihistamines, anti-cholinergic and vasoconstrictors. In recent years, increasing investigations of the nasal route have focused especially on nasal application for systemic drug delivery. Only a few nasal delivery systems used in experimental studies are currently on the market to deliver therapeutics into the nasal cavities, i.e. nasal drops as multiple or single-dose formulation, aqueous nasal sprays, a nasal gel pump, pressurized MDIs and dry powder inhalers. Intranasal delivery is currently being employed in treatments for migraine, smoking cessation, acute pain relief, osteoporosis, nocturnal ,enuresis and vitamin-B12 deficiency. Other examples of therapeutic areas under development or with potential for nasal delivery include cancer therapy, epilepsy, antiemetics, rheumatoid arthritis and insulin-dependent diabetes (Kublik and Vidgren, 1998).

Table- 1: Some marketed aqueous nasal products in the United States and United Kingdom

Product/ Manufacturer
Active Ingredient
Excipients Listed
Pack/Pump Information
AFRIN (DURATION)
Schering-Plough (U.S.)
Oxymetazoline 0.05%
Nasal
decongestant
BKC, Na2edta, PEG1450,
pov, PG, NaP
Plastic squeeze bottle
Spray pump bottle
Plastic squeeze bottle
Spray pump bottle
AFRIN SINUS
Schering-Plough (U.S.)

Oxymetazoline
0.05%
BKC, BA, Na2edta,
NaP, menthol, Tw80, PG camphor,
eucalyptol

Plastic squeeze bottle
AFRIN 4 hour
Schering-Plough (U.S.)

Phenylephrine HCl 0.5%
Nasal decongestant

BKC, Na2edta, PEG1450,
pov, PG, NaP, glycerine

Plastic squeeze bottle
ASTELIN, Wallace (U.S.) RHINOLAST
Asta Medica (UK)
Azelastine HCl 0.1% Antihistamine,
Mr = 418
BKC (125 g/mL),
Na2edta, HPMC, cit, NaP, NaCl, (pH 6.8)
Metered spray HDPE
bottle 0.137 L dose

BECONASE
GlaxoSmithKline (U.S./UK)
Beclomethasone
dipropionate 0.042%
(micronised)
SAI, Mr = 521
BKC, MCC, NaCMC,
dex, Tw80, PE-OH
(0.25% w/v), HCl,
(pH 4.5-7.0)

Amber neutral glass
bottle with metering
atomising pump and
nasal adapter
MIACALCIN nasal spray
Novartis (U.S.)
Calcitonin-salmon
32 amino acids,
Mr = 3527
BKC 0.1 mg/mL, NaCl
8.5 mg/mL, HCl, N2
Glass bottles, screw-on
pump
90 L per actuation
NASACORT AQ
Aventis (U.S.)
Triamcinolone acetonide
Corticosteroid, Mr = 435
BKC, MCC, NaCMC, Tw80, dex, HCl, Na2edta,
(pH 4.5-6.0)
HDPE bottle with
metered-dose pump
spray

NASCOBAL
Schwarz (U.S.)
Cyanocobalamin
Mr = 1355
BKC, MeC, NaCit, cit, glycerine, (pH 4.5-5.5)
Glass bottle dosing
500 g/100 L gel
NICOTROL NS
McNeil (U.S.)
Nicotine Mr = 162
NaP, citric acid, MePB,PrPB, NaCl, Na2edta,Tw80 (isotonic, pH 7)
Glass bottle, 50 L
actuation (droplet
size 8 m)

NOSTRILLA 12 h
Novartis (U.S.)
Oxymetazoline HCl
0.05%
BKC, glycine, sorbitol
White plastic bottle
PRIVINE Novartis
(U.S.)
Naphazoline HCl

BKC, NaP, Na2edta, NaCl

Bottle
SYNAREL
Searle (U.S./UK)
Nafarelin acetate,
Mr = 1113
BKC, acetic acid, NaOH, spray containing 200 g
Bottle delivering 100
spray containing 200 g nafarelin
DEXARHINASPRY
Boehringer Ingelheim
(UK)

Tramazoline
hydrochloride
120 g decongestant
BKC, NaCl, Tw80,
glycerol, NaOH
Amber Type I bottle
with 70 L metering
pump
IMIGRAN/IMITREX
GlaxoSmithKline (UK/U.S.)
Sumitriptan 20 mg
5HT1 receptor antagonist
KP, NaP, H2SO4, NaOH
100 L unit dose vial with rubber stopper and applicator
LOCABIOTAL
Servier (UK)

Fusfungine
antibiotic

EtOH, saccharin, IPM,
flavour

Type III glass bottle
(plasticised with
PVC)

Abbreviations: BA: benzyl alcohol; BHT: butylated hydroxytoluene; BKC: benzalkonium chloride; BzCl: benethonium chloride; CCS: croscarmellose sodium; cit: citric acid; dex: dextrose; IPM: isopropyl myristate; KP: potassium phosphates; MCC: microcrystalline cellulose; MeC: methyl cellulose; MePB: methyl parabens; Mr: relative molecular mass; NaCit: Na citrate; NaCMC: Na carboxymethylcellulose; Na2edta: disodium edetate; NaP: sodium phosphate; PEG: polyethylene glycol; PE-OH: phenylethyl alcohol; PG: propylene glycol; pov: povidone; PrPB: propyl parabens; SAI: steroidal anti-inflammatory; Tw: Tween (polysorbate)

2. NASAL ANATOMY AND PHYSIOLOGY INFLUENCING DRUG DELIVERY
2.1. Regulation of nasal airflow:
Nasal breathing is vital for most animals and also for human neonates in the first weeks of life. The nose is the normal and preferred airway during sleep, rest, and mild exercise up to an air volume of 20–30 l/min. It is only when exercise becomes more intense and air exchange demands increase that oral breathing supplements nasal breathing. The switch from nasal to oronasal breathing in young adults appears when ventilation is increased to about 35 l/min, about four times resting ventilation. More than 12,000 l of air pass through the nose every day (Cole, 1992). The functionality of the nose is achieved by its complex structure and aerodynamics. Amazingly, the relatively short air-path in the nose accounts for as much as 50–75 % of the total airway resistance during inhalation (Haight and 1983; Yu et al., 2008)

2.2. The nasal valve and aerodynamics:
The narrow anterior triangular dynamic segment of the nasal anatomy called the nasal valve is the primary flow-limiting segment, and extends anterior and posterior to the head of the inferior turbinate approximately 2–3 cm from the nostril opening (Cole, 2003). This narrow triangular-shaped slit acts as a dynamic valve to modify the rate and direction of the airflow during respiration (Fodil et al. 2005; Cole, 1992). Anatomical studies describe the static valve dimensions as 0.3–0.4 cm2 on each side, whereas acoustic rhinometry studies report the functional cross-sectional area perpendicular to the acoustic pathway to be between 0.5 and 0.6 cm2 on each side, in healthy adults, with no, or minimal gender differences (Djupesland et al., 2006). The flow rate during tidal breathing creates air velocities at gale force (18 m/s) and can approach the speed of a hurricane (32 m/s) at sniffing (Proctor and Swift, 1977). At nasal flow rates found during rest (up to 15 l/min), the flow regimen is predominantly laminar throughout the nasal passages. When the rate increases to 25 l/min, local turbulence occurs downstream of the nasal valve (Fodil et al. 2005). The dimensions can expand to increase airflow by dilator muscular action known as flaring, or artificially by mechanical expansion by internal or external dilators (Mann et al., 1977; Djupesland et al., 2001). During inhalation, Bernoulli forces narrow the valve progressively with increasing inspiratory flow rate and may even cause complete collapse with vigorous sniffing in some subjects. During exhalation, the valve acts as a "brake" to maintain a positive expiratory airway pressure that helps keep the pharyngeal and lower airways open and increase the duration of the expiratory phase. This "braking" allows more time for gas exchange in the alveoli and for retention of fluid and heat from the warm saturated expiratory air (Hairfield et al., 1987). In fact, external dilation of narrow noses in obstructive sleep apnea patients had beneficial effects, whereas dilation of normal noses to "supernormal" dimensions had deleterious effects on sleep parameters (Djupesland et al., 2001). However, in the context of nasal drug delivery, the small dimensions of the nasal valve, and its triangular shape that narrows further during nasal inhalation, represent important obstacles for efficient nasal drug delivery.


Figure-1: The complex anatomy of the nasal airways and paranasal sinuses


Figure- 2: Illustration of the nasal delivery process.
2.3. The nasal mucosa—filtration and clearance:
The region anterior to the valve called the vestibule is lined by non-ciliated squamous epithelium that in the valve region gradually transitions into ciliated epithelium typical of the ciliated respiratory epithelium posterior to the valve region (Mygind and Dahl, 1998). Beyond the nasal valve, the nasal turbinates divide the nasal cavity into slit-like passages with much larger crosssectional area and surface area (Figs. 1, 2 and 3). Here, the predominantly laminar airflow is slowed down to speeds of 2–3 m/s and disrupted with eddies promoting deposition of particles carried with the air at and just beyond the valve region (Cole, 1992). The ciliated respiratory mucosa posterior to the nasal valve is covered by a protective mucous blanket designed to trap particles and microorganisms (Mygind and Dahl, 1998). The beating action of cilia moves the mucous blanket towards the nasopharynx at an average speed of 6 mm/min (3–25 mm/min) (Proctor, 1982; Halama et al., 1990). The large surface area and close contact enables effective filtering and conditioning of the inspired air and retention of water during exhalation (Figs. 1, 2 and 3).Oral breathing increases the net loss of water by as much as 42 % compared to nasal breathing (Svensson et al., 2006). The nasal passages were optimized during evolution to protect the lower airways from the constant exposure to airborne pathogens and particles.

Specifically, particles larger than 3–10 μm are efficiently filtered out and trapped by the mucus blanket (Mygind and Dahl, 1998). The nose also acts as an efficient "gas mask" removing more that 99 % of water-soluble, tissue-damaging gas like sulfur dioxide (Andersen et al., 1974). Infective agents are presented to the abundant nasal immune system both in the mucous blanket, in the mucosa, and in the adjacent organized lymphatic structures making the nose attractive for vaccine delivery with potential for a longstanding combination of systemic and mucosal immune responses (Brandtzaeg, 2003). The highly vascularized respiratory mucosa found beyond the valve allows exchange of heat and moisture with the inspired air within fractions of a second, to transform cold winter air into conditions more reminiscent of a tropical summer (Mygind and Dahl, 1998).

2.4. The nasal cycle:
The physiological alternating congestion and decongestion observed in at least 80% of healthy humans is called the nasal cycle (Baraniuk, 2008). The nasal cycle was first described in the rhinological literature by a German physician in 1895, but was recognized inYoga literature centuries before (Cole, 1992). Healthy individuals are normally unaware of the spontaneous and irregular reciprocal 1–4-h cycling of the nasal caliber of the two individual passages, as the total nasal resistance remains fairly constant .The autonomic cyclic change in airflow resistance is mainly dependent on the blood content of the submucosal capacitance vessels that constitute the erectile component at critical sites, notably the nasal valve region. Furthermore, the erectile tissues of the septal and lateral walls and the turbinates respond to a variety of stimuli including physical and sexual activity and emotional states that can modify and override the basic cyclic rhythm (Yilmaz and Naclerio, 2011). The cycle is present during sleep, but overridden by pressures applied to the lateral body surface during recumbency to decongest the uppermost/contralateral nasal passage. It has been suggested that this phenomenon causes a person to turn from one side to the other while sleeping (Cole and Haight, 1986).

The cycle is suppressed in intubated subjects, but restored by resumption of normal nasal breathing. The cycle may also cause accumulation of nitric oxide (NO) in the congested passage and adjacent sinuses and contribute to defense against microbes through direct antimicrobial action and enhanced mucociliary clearance (Djupesland et al., 2011). Measurements have shown that the concentration of NO in the inspired air is relatively constant due to the increase in NO concentration within the more congested cavity, which nearly exactly counterbalances the decrease in nasal airflow (Qian et al., 2011). In some patients, as a result of structural deviations and inflammatory mucosal swelling, the nasal cycle may become clinically evident and cause symptomatic obstruction. Due to the cycle, one of the nostrils is considerably more congested than the other most of the time, and the vast majority of the airflow passes through one nostril while the other remains quite narrow especially at the valve region (Cole, 1992). Consequently, the nasal cycle contributes significantly to the dynamics and resistance in the nasal valve region and must be taken into consideration when the efficiency of nasal drug delivery devices is considered.

2.5. Nasal and sinus vasculature and lymphatic system:
For nasally delivered substances, the site of deposition may influence the extent and route of absorption along with the target organ distribution. Branches of the ophthalmic and maxillary arteries supply the mucous membranes covering the sinuses, turbinates, meatuses, and septum, whereas the superior labial branch of the facial artery supplies the part of the septum in the region of the vestibule. The turbinates located at the lateral nasal wall are highly vascularized with a very high blood flow and act as a radiator to the airway. They contain erectile tissues and arteriovenous anastomoses that allow shunting and pooling related to temperature and water control and are largely responsible for the mucosal congestion and decongestion in health and disease (Jones, 2011). Substances absorbed from the anterior regions are more likely to drain via the jugular veins, whereas drugs absorbed from the mucosa beyond the nasal valve are more likely to drain via veins that travel to the sinus cavernous, where the venous blood comes in direct contact with the walls of the carotid artery.

A substance absorbed from the nasal cavity to these veins/venous sinuses will be outside the blood–brain barrier (BBB), but for substances such as midazolam, which easily bypass the BBB, this route of local "counter-current transfer" from venous blood may provide a faster and more direct route to the brain. Studies in rats support that a preferential, first-pass distribution to the brain through this mechanism after nasal administration may exist for some, but not all small molecules. The authors suggested that this countercurrent transport takes place in the area of the cavernous sinus carotid artery complex, which has a similar structure in rat and man, but the significance of this mechanism for nasally delivered drugs has not been demonstrated in man (Jensen and Larsen, 2000; Jensen et al., 2001). The lymphatic drainage follows a similar pattern as the venous drainage where lymphatic vessels from the vestibule drain to the external nose to submandibular lymph nodes, whereas the more posterior parts of the nose and paranasal sinuses drain towards the nasopharynx and internal dee lymph nodes. In the context of nasal drug delivery, perivascular spaces along the olfactory and trigeminal nerves acting as lymphatic pathways between the CNS and the nose have been implicated in the transport of molecules from the nasal cavity to the CNS (Dhuria et al., 2009).

2.6. Innervations of the nasal mucosa:
The nose is also a delicate and advanced sensory organ designed to provide us with the greatest pleasures, but also to warn and protect us against dangers. An intact sense of smell plays an important role in both social and sexual interactions and is essential for quality of life. The sense of smell also greatly contributes to taste sensations (Landis et al., 2010). Taste qualities are greatly refined by odor sensations, and without the rich spectrum of scents, dining and wining and life in general would become dull (Brant, 2000). The olfactory nerves enter the nose through the cribriform plate and extend downwards on the lateral and medial side of the olfactory cleft. Recent biopsy studies in healthy adults suggest that the olfactory nerves extend at least 1–2 cm further anterior and downwards than the 8–10 mm described in most textbooks (see Figs. 1 and 2) (Feron et al., 1988; Leopold et al., 2000). The density decreases, but olfactory filaments and islets with olfactory epithelium are found in both the anterior and posterior parts at the middle turbinate. In addition, sensory fibers of both the ophthalmic and maxillary branches of the trigeminal nerve contribute to olfaction by mediating a "common chemical sense" (Hummel and Livermore, 2002). Branches of the ophthalmic branch of the trigeminal nerve provide sensory innervation to the anterior part of the nose including the vestibule, whereas maxillary branches innervate the posterior part of the nose as well as the regions with olfactory epithelium. The olfactory and trigeminal nerves mutually interact in a complex manner. The trigeminal system can modulate the olfactory receptor activity through local peptide release or via reflex mechanisms designed to minimize the exposure to and effects of potentially noxious substances (Hummel and Livermore, 2002).

This can occur by alteration of the nasal patency and airflow and through changes in the properties of the mucous blanket covering the epithelium. Trigeminal input may amplify odorous sensation through perception of nasal airflow and at the chemosensory level. Interestingly, an area of increased trigeminal chemosensitivity is found in the anterior part of the nose, mediating touch, pressure, temperature, and pain (Hummel and Livermore, 2002). Pain receptors in the nose are not covered by squamous epithelium, which gives chemical stimuli almost direct access to the free nerve endings. In fact, loss of trigeminal sensitivity and function, and not just olfactory nerve function, may severely reduce the sense of smell (Husner et al., 2006). This should not be forgotten when addressing potential causes of reduced or altered olfaction.

2.7. The sensitivity of the nasal mucosa as a limiting factor:
In addition to the limited access, obstacles imposed by its small dimensions and dynamics, the high sensitivity of the mucosa in the vestibule and in the valve area is very relevant to nasal drug delivery. Direct contact of the tip of the spray nozzle during actuation, in combination with localized concentrated anterior drug deposition on the septum,may createmechanical irritation and injury to the mucosa resulting in nosebleeds and crusting, and potentially erosions or perforation (Waddell et al., 2003). Furthermore, the Drug Deliv. and Transl. Res. high-speed impaction and low temperature of some pressurized devices may cause unpleasant sensations reducing patient acceptance and compliance. The role of the high sensitivity of the nasal mucosa as a natural nasal defense is too often neglected when the potential of nasal drug delivery is discussed, in particular when results from animal studies, cast studies, and computer fluid dynamics (CFD) are evaluated. Exposure to chemicals, gases, particles, temperature and pressure changes, as well as direct tactile stimuli, may cause irritation, secretion, tearing, itching, sneezing, and severe pain (Hummel and Livermore, 2002). Sensory, motor, and parasympathetic nerves are involved in a number of nasal reflexes with relevance to nasal drug delivery (Yilmaz and Naclerio, 2011). Such sensory inputs and related reflexes are suppressed by the anesthesia and/or sedation often applied to laboratory animals, potentially limiting the clinical predictive value of such studies. Further, the lack of sensory feedback and absence of interaction between the device and human subjects/ patients are important limitations of in vitro testing of airflow and deposition patterns in nasal casts and in CFD simulation of deposition. Consequently, deposition studies in nasal casts and CFD simulation of airflow and deposition are of value, but their predictive value for the clinical setting are all too often overestimated.

2.8. Targeted nasal delivery:
For most purposes, a broad distribution of the drug on the mucosal surfaces appears desirable for drugs intended for local action or systemic absorption and for vaccines (Vidgren and Kublik, 1998). However, in chronic sinusitis and nasal polyposis, targeted delivery to the middle and superior meatuses where the sinus openings are, and where the polyps originate, appears desirable (Laube, 2007; Aggrawal et al., 2004). Another exception may be drugs intended for "nose-to-brain" delivery, where more targeted delivery to the upper parts of the nose housing the olfactory nerves has been believed to be essential. However, recent animal data suggest that some degree of transport can also occur along the branches of the first and second divisions of the trigeminal nerve innervating most of the mucosa at and beyond the nasal valve (Johnson et al., 20
3. MECHANISM OF NASAL ABSORPTION
The absorbed drugs from the nasal cavity must pass through the mucus layer; it is the first step in absorp-tion. Small, unchanged drugs easily pass through this layer but large, charged drugs are difficult to cross it. The principle protein of the mucus is mucin, it has the tendency to bind to the solutes, hindering diffusion. Additionally, structural changes in the mucus layer are possible as a result of environmental changes (i.e. pH, temperature, etc.) (Illum et al., 1999). So many ab-sorption mechanisms were established earlier but only two mechanisms have been predominantly used, such as:

3.1. First mechanism:
It involves an aqueous route of transport, which is also known as the paracellular route but slow and passive. There is an inverse log-log correlation between intranasal absorption and the molecular weight of water-soluble com-pounds. The molecular weight greater than 1000 Daltons having drugs shows poor bioavailability (Aurora, 2002).

3.2. Second mechanism:
It involves transport through a lipoidal route and it is also known as the transcellular process. It is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. Drug also cross cell membranes by an active transport route via carrier-mediated means or transport through the opening of tight junctions (Buri, 1966).


4. LIQUID NASAL FORMULATION DEVICES
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 (Zia et al., 1993) and the reduced chemical stability of the dissolved drug substance and the short residence time of the formulation in the nasal cavity are major disadvantages of liquid formulations (Illum et al., 1987; Hardy et al., 1985). The several type dosage forms available in liquid form are described below.

4.1. Instillation and rhinyle catheter:
Catheters are used to deliver the drops to a specified region of nasal cavity easily. Place the formulation in the tube and kept tube one end was positioned in the nose, and the solution was delivered into the nasal cavity by blowing through the other end by mouth (Hughes et al., 1993; Harris et al., 1986). Dosing of catheters is determined by the filling prior to administration and accuracy of the system and this is mainly used for experimental studies only.

4.2. 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 (Knoch and Finlay, 2002). Nebulizers accept their medicine in the form of a liquid solution, which is often loaded into the device upon use. Corticosteroids and Bronchodilators such as salbutamol (Albuterol USAN) are often used, and sometimes in combination with ipratropium. The reason these pharmaceuticals are inhaled instead of ingested is in order to target their effect to the respiratory tract, which speeds onset of action of the medicine and reduces side effects, compared to other alternative intake routes This device is not suitable for the systemic delivery of drug by patient himself.

4.3. 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. Dose accuracy and deposition of liquids delivered via squeezed nasal bottles are strongly dependent on the mode of administration. The differences between vigorously and smoothly pressed applications influence the dose as well as the droplet size of the formulation. Thus the dose is hard to control. Therefore squeezed bottles with vasoconstrictors are not recommended to be used by children (Mygind and Vesterhauge, 1978).

4.4. Metered-dose pump sprays:
Most of the pharmaceutical nasal preparations on the market containing solutions, emulsions or 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. The dose accuracy of metered dose pump sprays is dependent on the surface tension and viscosity of the formulation. For solutions with higher viscosity, special pump and valve combinations are on the market (Knoch and Finlay, 2002).



5. FORMULATION SELECTION CONSIDERATIONS
There are many factors to be considered in the successful "product design" and development of an aqueous nasal formulation. A typical development programme should consider the technical challenges of the molecule and balance these against the clinical and marketing requirements for the product. Several issues need to be addressed. For example, is the drug to be administered to one or two nostrils, is the drug sufficiently soluble to permit administration as a solution, and is the dose feasible (e.g., are there existing formulations for similar molecules)? If the dose levels are limited, solubility enhancement may be possible with permitted excipients, or permeability enhancers may be required. If solubility is limited, a suspension product is the only alternative, but there are more technical challenges than are present for solution products (Day, 2004).


5.1. Preformulation and Bulk Drug Properties:
A preformulation package provides essential information on the physicochemical properties of the drug, such as pKa, aqueous solubility, aqueous stability, light stability, and lipophilicity (this may predict potential for binding to plastic/rubber pump components). The pKas of any ionisable groups are particularly important as they affect stability, solubility and lipophilicity and should indicate the optimum pH for the nasal solution. For physiological reasons, formulated products are usually in the range of pH 4.0-7.4. If the drug is insufficiently soluble to allow delivery of the required dose as a solution (the maximum delivered dose for each nostril is 200 L), then a suspension formulation will be required. There are additional issues for suspension products, for example crystal growth, physical stability, resuspension, homogeneity and dose uniformity. Suspension products will also require information on density, particle size distribution, particle morphology, solvates and hydrates, polymorphs, amorphous forms, moisture and/or residual solvent content and microbial quality (sterile filtration of the bulk liquid during manufacture is not feasible) (Day, 2004).

5.2. Drug concentration, dose and dose volume:
Drug concentration, dose and dose volume of administration are three interrelated parameters that impact the performance of nasal delivery system. Nasal absorption of L-tyrosine was shown to increase with drug concentration in nasal perfusion experiments. However, in another study, aminopyrine was found to absorb at a constant rate as a function of concentration (Sarasija and Shyamala, 2005). Several studies have reported the effect of drug dose on nasal absorption, e.g. calcitonin, GnRH agonist, desmopresin, secretin. In general, higher nasal absorption or therapeutic effect was observed with increasing dose. It is important to note how the dose is varied. If the drug is increasing by increasing formulation volume, there may be a limit as to what extent nasal absorption can be increased. The nostril can retain only a limited volume, beyond which a formulation wile drain out of the nasal cavity. The ideal dose volume range is 0.05-0.15 ml with an upper limit of 0.20 ml (Dua et al., 1997)

5.3. pH of the formulation:
Both the pH of the nasal cavity and pKa of a particular drug need to be considered to optimize systemic absorption. Nasal irritation is minimized when products are delivered with pH, in the range of 4.5 to 6.5. Also, volume and concentration are important to consider. The delivery volume is limited by the size of the nasal cavity. An upper limit of 25 mg/dose and a volume of 25 to 200 μl/ nostril have been suggested:

To avoid irritation of nasal mucosa,
To allow the drug to be available in unionized form for absorption,
To prevent growth of pathogenic bacteria in the nasal passage,
To maintain functionality of excepients such as preservatives, and
To sustain normal physiological ciliary movement (Kushwaha et al., 2011).

5.4. Buffer capacity:
Nasal formulations are generally administered in small volumes ranging from 25 to 200μL. Hence, nasal secretions may alter the pH of the administered dose. This can affect the concentration of unionized drug available for absorption. Therefore, an adequate formulation buffer capacity may be required to maintain the pH in-situ (Kushwaha et al., 2011).

5.5. Viscosity:
A higher viscosity of the formulation increases contact time between the drug and the nasal mucosa thereby increasing the time for permeation. At the same time, highly viscous formulations interfere with the normal functions like ciliary beating or mucociliary clearance and thus alter the permeability of drugs (Jadhav et al.,2007)

5.6. Formulation osmolarity:
Drug absorption can be affected by tonicity of the formulation. Shrinkage of the epithelial cells has been observed in the presence of hypertonic solution. Hypertonic saline solution also inhibits or ceases ciliary activity. Low pH has similar effect as that of hypertonic solutions. Generally an isotonic formulation is preferred (Behl et al., 1998)

5.7. Selection of Excipients:
Aqueous nasal products are listed as marketed in the United States and the United Kingdom. This table shows a relatively limited range of excipients used and accepted by the regulatory authorities. Excipients featured in marketed nasal products in the United States are given (FDA 1996). According to the pH chosen and the ionisation properties of the drug, an appropriate buffer system are usually incorporated, often a mixed phosphate buffer system. However, if it is appropriate to choose the pKa of the drug itself, then this becomes a self-buffered system. If it is feasible, there are advantages in choosing a pH equal to the pKa; during manufacturing, it is easier to titrate to the target pH in the region of maximum buffer capacity (pKa). Aqueous nasal preparations are usually isotonic to ensure physiological acceptability. A choice needs to be made between ionic tonicity (e.g., saline) or non-ionic tonicity (e.g., dextrose). Flavours or sweetening agents are sometimes added to a formulation to mask the taste, a small proportion of which may be swallowed following nasal delivery (Batts et al, 1991). Perceptions of taste do vary with age, and therefore paediatric formulations may have to be slightly different from adult formulations. Sometimes a metal-chelating agent (e.g., disodium edetate) is included. This may also enhance preservative efficacy. Oxygen is sometimes excluded by means of a nitrogen purge, and antioxidants may also be included to improve stability. Suspension systems usually require an appropriate surfactant and viscosity adjuster.

5.8. Permeation Enhancers:
Small and large hydrophilic drugs may be poorly permeable across nasal epithelium and may show an insufficient bioavailability. Complete mechanism of drug absorption enhancement through nasal mucosa is not known. However, various mechanisms such as increase in the membrane fluidity, creating transient hydrophilic pores, decreasing the viscosity of mucus layer and opening up of tight junctions are the proposed mechanism of permeation enhancers which improve the bioavailability of nasal dosage forms (Chien, 1992). Some of the permeation enhances like bile salts and fusidic acid derivatives can also inhibit the enzymatic activity in the membrane, thereby improving bioavailability. Even though nasal permeation enhancers can improve the therapeutic efficacy of drug products, its toxicity should be considered while developing dosage form. One of the most common and frequently reported problems with permeation enhancers is the nasal irritation during administration of nasal dosage form (Chien, 1992). The ideal characteristic of nasal permeations is as follows.

It should be pharmacologically inert.
It should be non-allergic, non-toxic and non-irritating. · It should be highly potent.
It should be compatible with a wide variety of drugs and excepients.
It should be odourless, colorless and tasteless.
It should be inexpensive and readily available in highest purity.
It should be accepted by many regulatory agencies all around the world.

The permeation enhancer not only can lead to improvement in absorption and bioavailability but also provide uniform dosing efficacy. Their non specific action, long term toxicity, and nasal irritation are the major hurdles, which affects the clinical applicability of permeation enhancers in the development of nasal dosage form. Cyclodextrins act as solubilizer and permeation enhancer for nasal drug delivery and they are well tolerated in humans (Merkus et al., 1999).
Amongst cyclodextrin, beta cyclodextrin is being considered to have Generally Recognised As Safe (GRAS) status. All other cyclodextrin are experimental material at this time. Schipper and cowokers studied the beta cyclodextrin as permeation enhancer for nasal drug delivery of insulin30. The administration of insulin with 5% solution of dimethyl beta cyclodextrin did not enhance the absorption of insulin in rabbits, whereas powder dosage form significantly enhances the bioavailability of insulin in rabbits (Schipper et al., 1990). Several compounds such as calcitonin, cartison, diazepam and naproxen investigated for their nasal bioavailability enhancement using cyclodextrin as the permeation enhancer. Surfactants are the most effective permeation enhancers but the issues like nasal irritation, epithelial toxicity, ciliostatic activity are the barriers for usage of surfactant as a nasal permeation enhancers. The extent of nasal absorption of insulin from nebulizer spray was observed to be pH dependent indicating maximum absorption at acidic pH.
However, nasal absorption of insulin with surfactants like saponin, BL-9 and glycolate was significantly increased even at acidic pH, which correlated with hypoglycaemic activity. Comparative pharmacokinetics of intranasal delivery of salmon calcitonin was studied with various surfactants. A 10-fold increase serum calcitonin levels over control groups (calcitonin without surfactants) was observed in the formulations incorporated with surfactant. Laureth-9 was used as permeation enhancer to improve the bioavailability of insulin. The bile salts are believed to improve the bioavailability of both solubilisation of insulin and by direct effect of surfactant on the cell membrane (Angust and Rogers, 1988).

5.9. Preservatives:
If a traditional multidose nasal spray is used, then a preservative will have to be included in the formulation, and preservative challenge testing will be required (e.g., in accordance with U.S. Pharmacopeia (USP) 51 Antimicrobial Effectiveness Testing).The test is usually performed over 4 weeks using 50 mL of formulation, covering five organisms. Testing is required at zero time (initial) and at the 1, 2 and 3 year time-point of the stability programme. This work must also cover concentration ranges of preservative at the limits of specification. It is important to consider the effect of pH on preservative efficacy. The most common preservatives in aqueous nasal formulations are benzalkonium chloride (BKC) and phenylethyl alcohol. BKC is often chosen because it is a good preservative, but it does have two known complications. The benzalkonium cation can react with anionic actives and can lead to a reduction in either active potency or preservative efficacy. In addition to this, it is reported that BKC can have a long-term adverse effect on nasal mucosa (Hallen and Graf , 1995).

Clinically, this was exhibited by increased nasal stuffiness from symptom scores and swelling of the nasal mucosa. This may be related to the observed experimental effect of BKC on nasal cilia (Batts et al., 1989; Batts et al., 1990; Deitmer and Scheffler, 1993; Bernstein, 2000). Preservative efficacy testing can produce variable results, and it is important to evaluate several alternatives during formulation development (Hodges et al., 1996). Some traditional preservatives have now become less popular (e.g., the mercury-based preservatives thiomersal and phenylmercuric nitrate) because of toxicological concern with chronic use. It is vital that the international acceptability of a preservative is checked.





Table-2: Common excipients used in aqueous nasal products (FDA, 1996).
Excipient
Function
Typical Concentration
Acetic and citric acids
pH adjustment/buffer
0.12%/0.10%
NaOH/HCl
pH adjustment
No range
Edetate disodium
Metal chelator/preservative enhancer
0.01%
Benzalkonium chloride
Preservative (known effect on cilia)
0.01-0.02% w/v
Benzethonium chloride
Preservative
No range
Benzyl alcohol
Preservative
Not listed by FDA
Chlorobutanol
Preservative (known effect on cilia)
0.05-0.1%
Methylparaben
Preservative (known effect on cilia)
0.033%
Phenylethyl alcohol
Preservative
0.25%
Phenylmercuric acetate
Preservative (known effect on cilia)
Not listed by FDA
Propylparaben
Preservative (known effect on cilia)
0.017%
Thimerosal
Preservative (no effect on cilia at 0.01%)
Not listed by FDA
Potassium chloride
Tonicity adjustment
Not listed by FDA
Sodium chloride
Tonicity adjustment
0.5-0.9%
Me-OH-Pr cellulose
Viscosity adjustment
1%
Na CMC
Viscosity adjustment
1%
Microcrystalline cellulose
Viscosity adjustment
1%
Ethanol
Solvent
No range
Glycerol
Solvent/tonicity adjustment
1.0-2.5%
Glycine
Solvent/tonicity adjustment
No range
PEG (mixed)
Solvent
5%
PG
Solvent
10%
Glyceryl dioleate
Solvent
10%
Glyceryl monoleate
Surfactant
7%
Lecithin
Surfactant
5%
Polysorbate 20 & 80 Triglycerides
Surfactant
2%
Menthol
Flavouring agent
No range
Saccharin sodium
Flavouring agent (sweetener)
No range

5.10. Stability and Compatibility:
Both the formulation and the delivery device together need to be considered in the stability testing programme. The active must be compatible with the excipients, but in addition, both must be compatible with the delivery device. Stability testing must be conducted according to International Conference on Harmonisation (ICH) guidelines, depending on the intended territories. Specific considerations relevant to the pack are the type of plastic bottle (e.g., high density polyethylene [HDPE]) or glass bottle (e.g., amber), binding of active to the bottle or pump components, and the appearance of leachables and extractables from the plastics and elastomers used in the delivery device (Day, 2004).

5.11. Processing Issues:
It is essential to look forward to the manufacturing and processing issues which will be encountered during development of a nasal product, particularly the effect of scaling-up from the laboratory (e.g., 5 L scale) to stability and small-scale clinical trial (e.g., 50 L) through to production scale (e.g., 500 L). For solution products, it is important to consider the rate of dissolution and mixing time required. Filter (membrane) compatibility data should be generated, if possible using a filtration system that can be appropriately scaled-up from laboratory to production. A membrane system based upon polyvinylidene fluoride (PVDF), polysulphone or polycarbonate is often chosen. The availability of this information is especially important for peptide drugs, for which there are often issues of stability and adsorption. For suspension products, there are particular issues already mentioned in the section "Preformulation and Bulk Drug Properties". In general, there are more issues in scaling-up suspension products than there are for solution products. Such issues are the need to "wet" larger quantities of drug, the possibility of foaming and homogeneity during the extended time of filling (Day, 2004).

6. DEVICE SELECTION CONSIDERATIONS
For the successful development of a nasal spray it is important to understand the basic mechanisms of such a device to recognize the cliffs which must be avoided. Of course a product intended to be administered as a nasal spray should have no unpleasant smell, should not be irritating and even long term treatment should have no negative effects on the nasal mucosa (e.g. ulceration, loss of sense of smell). There should be also no safety concern, if a dose is unintentionally shot into the eyes.

Standard spray pumps will deposit most of the sprayed dose into the anterior region of the nasal cavity. Surface tension of the droplets and mucus layer will cause the immediate spread of the spray. Afterwards mucociliar clearance will distribute the liquid layer within the nasal cavity. Since the nasal mucus layer is continuously renewed and discarded into the throat, the nasal dwelling time of the administered drug depends on how fast it dissolves within the mucus layer and penetrates into the mucosa (Suman et al., 2002). Although authorities require a lot of data to describe nasal spray devices, for deposition efficiency the plume angle and administration angle are critical factors, while many other spray parameters, including particle size, have relatively minor influences on deposition within the nasal cavity (Foo et al., 2007).
The three key requirements of the nasal delivery device are-
Stability with the formulated product
User-friendly design for patient compliance
Reliability in use.
The longest-established systems typically dispense nasal drops or a crude spray via a flexible plastic squeeze bottle. These systems are often described as "open", since they readily allow contaminated air back into the bottle after discharge. Bacteria can thus enter the system and, whilst the use of preservatives can minimise the risk of growth, these systems are now regarded as the least satisfactory design. In addition, the instillation of drops per se into the nasal cavity is inefficient because the drug solution is inevitably cleared along the floor of the nasal cavity, with a correspondingly short residence time. Squeeze-bottle systems that dispense a spray (as opposed to drops) have better distribution within the nasal cavity, but these suffer from imprecise dosing. Key dosing parameters such as spray angle, droplet size and delivered dose (volume or weight) are all subject to variability due to (a) the squeeze pressure applied to the bottle and (b) the ratio of liquid to air in the squeeze bottle (which changes significantly during the life of the bottle) (Day, 2004).



Figure-3: Parts for a standard pump and how it looks like when assembled. On the right side: soaking of parts in formulation to check compatibility. For demonstration just parts for one pump are depicted.

Recent innovations in pump design have allowed preservative-free formulations to be de-
veloped. Such designs have obvious advantages in the avoidance of the use of preservatives,
some of which can affect mucociliary clearance, and some of which can interact with active
ingredients. Another advantage is that a new formulation with no preservative will usually
achieve a patent extension over the existing product. These systems can only exist if the contents of the nasal spray bottle are sealed to ingress from the environment. Two of the companies that have developed a preservative-free system are Pfeiffer and Valois. The Pfeiffer system uses a sealing mechanism in the nasal actuator to prevent air from entering the container upon actuation; air is allowed to enter the container and equalise with atmospheric pressure through a microbiological filter. A second approach is to use a collapsible bag (containing the formulation) inside the rigid bottle. The bag remains sealed and clean and the displaced solution is compensated for by ingress of air into the space between the bag and the bottle. A third approach is to adopt a sliding piston (analogous to the displacement of a syringe); this has the advantage of allowing the device to be used at any angle (Bommer, 1999).



Figure- 4: Cross-section of a traditional nasal device.

6.1. Devices for liquid formulations:
The liquid nasal formulations are mainly aqueous solutions, but suspensions and emulsions can also be delivered. Liquid formulations are considered convenient particularly for topical indications where humidification counteracts the dryness and crusting often accompanying chronic nasal diseases (Vidgren and Kublik, 1998). In traditional spray pump systems, preservatives are typically required to maintain microbiological stability in liquid formulations. Studies in tissue cultures and animals have suggested that preservatives, like benzalkonium chloride in particular, could cause irritation and reduced ciliary movement. However, more recent human studies based on long-term and extensive clinical use have concluded that the use of benzalkonium chloride is safe and well tolerated for chronic use (Marple et al., 2004). For some liquid formulations, in particular peptides and proteins, limited stability of dissolved drug may represent a challenge (Illum, 2003).

Drops delivered with pipette:
Drops and vapor delivery are probably the oldest forms of nasal delivery. Dripping breast milk has been used to treat nasal congestion in infants, vapors of menthol or similar substances were used to wake people that have fainted, and both drops and vapors still exist on the market. Drops were originally administered by sucking liquid into a glass dropper, inserting the dropper into the nostril with an extended neck before squeezing the rubber top to emit the drops. For multi-use purposes, drops have to a large extent been replaced by metered-dose spray pumps, but inexpensive single-dose pipettes produced by "blow-fill-seal" technique are still common for OTC products like decongestants and saline. An advantage is that preservatives are not required. In addition, due to inadequate clinical efficacy of spray pumps in patients with nasal polyps, a nasal drop formulation of fluticasone in single-dose pipettes was introduced in the EU for the treatment of nasal polyps. The rationale for this form of delivery is to improve drug deposition to the middle meatus where the polyps emerge (Penttila et al., 2000; Keith et al., 2000). However, although drops work well for some, their popularity is limited by the need for head-down body positions and/or extreme neck extension required for the desired gravity-driven deposition of drops (Aggrawal et al., 2004; Merkus et al., 2006). Compliance is often poor as patients with rhinosinusitis often experience increased headache and discomfort in head-down positions.

Delivery of liquid with rhinyle catheter and squirt tube:
A simple way for a physician or trained assistant to deposit drug in the nose is to insert the tip of a fine catheter or micropipette to the desired area under visual control and squirt the liquid into the desired location. This is often used in animal studies where the animals are anesthetized or sedated, but can also be done in humans even without local anesthetics if care is taken to minimize contact with the sensitive mucosal membranes (Bakke, 2006). This method is, however, not suitable for self-administration. Harris et al. (Harris et al., 1986) described a variant of catheter delivery where 0.2 ml of a liquid desmopressin formulation is filled into a thin plastic tube with a dropper. One end of the tube is positioned in the nostril, and the drug is administered into the nose as drops or as a "liquid jet" by blowing through the other end of the thin tube by the mouth (Harris et al., 1986). Despite a rather cumbersome procedure with considerable risk of variability in the dosing, desmopressin is still marketed in some countries with this rhinyle catheter alongside a nasal spray and a tablet for treatment of primary nocturnal enuresis, Von Willebrand disease, and diabetes insipidus.

Squeeze bottles:
Squeeze bottles are mainly used to deliver some over-thecounter (OTC) products like topical
decongestants. By squeezing a partly air-filled plastic bottle, the drug is atomized when delivered from a jet outlet. The dose and particle size vary with the force applied, and when the pressure is released, nasal secretion and microorganisms may be sucked into the bottle. Squeeze bottles are not recommended for children (Vidgren and Kublik, 1998).

Metered-dose spray pumps:
Metered spray pumps have, since they were introduced some four decades ago, dominated the nasal drug delivery market. The pumps typically deliver 100 μl (25–200 μl) per spray, and they offer high reproducibility of the emitted dose and plume geometry in in vitro tests. The particle size and plume geometry can vary within certain limits and depend on the properties of the pump, the formulation, the orifice of the actuator, and the force applied (Vidgren and Kublik, 1998). Traditional spray pumps replace the emitted liquid with air, and preservatives are therefore required to prevent contamination. However, driven by the studies suggesting possible negative effects of preservatives, pump manufacturers have developed different spray systems that avoid the need for preservatives. These systems use a collapsible bag, a movable piston, or a compressed gas to compensate for the emitted liquid volume (Vidgren and Kublik, 1998). The solutions with a collapsible bag and a movable piston compensating for the emitted liquid volume offer the additional advantage that they can be emitted upside down, without the risk of sucking air into the dip tube and compromising the subsequent spray. This may be useful for some products where the patients are bedridden and where a head down application is recommended. Another method used for avoiding preservatives is that the air that replaces the emitted liquid is filtered through an aseptic air filter. In addition, some systems have a ball valve at the tip to prevent contamination of the liquid inside the applicator tip. These preservative-free pump systems become more complex and expensive, and since human studies suggest that preservatives are safe and well tolerated, the need for preservative-free systems seems lower than previously anticipated (Marple et al., 2004). More recently, pumps have been designed with side-actuation and introduced for delivery of fluticasone furoate for the indication of seasonal and perennial allergic rhinitis (Berger et al., 2007). The pump was designed with a shorter tip to avoid contact with the sensitive mucosal surfaces. New designs to reduce the need for priming and re-priming, and pumps incorporating pressure point features to improve the dose reproducibility and dose counters and lock-out mechanisms for enhanced dose control and safety are available. Importantly, the in vivo deposition and clinical performance of metered-dose spray pumps can be enhanced for some applications by adapting the pumps to a novel breathpowered "Bi-Directional " delivery technology described in more detail below (Djupesland et al., 2006).

Single- and duo-dose spray devices:
Metered-dose spray pumps require priming and some degree of overfill to maintain dose conformity for the labeled number of doses. They are well suited for drugs to be administered daily over a prolonged duration, but due to the priming procedure and limited control of dosing, they are less suited for drugs with a narrow therapeutic window. For expensive drugs and vaccines intended for single administration or sporadic use and where tight control of the dose and formulation is of particular importance, single-dose or duo-dose spray devices are preferred. A simple variant of a single-dose spray device (MAD) is offered by LMA (LMA, Salt Lake City, UT, USA; www.lmana.com). A nosepiece with a spray tip is fitted to a standard syringe. The liquid drug to be delivered is first drawn into the syringe and then the spray tip is fitted onto the syringe. This device has been used in academic studies to deliver, for example, a topical steroid in patients with chronic rhinosinusitis and in a vaccine study (Kanowitz et al., 2008; Renteria et al., 2010). A pre-filled device based on the same principle for one or two doses (Accuspray , Becton Dickinson Technologies, Research Triangle Park, NC, USA) is used to deliver the influenza vaccine FluMist, approved for both adults and children in the US market (Nichol et al., 1999; Belshe et al., 2007). A similar device for two doses was marketed by a Swiss company for delivery of another influenza vaccine a decade ago. This vaccine was withdrawn due to occurrence of adverse events (Bell's palsy) potentially related to the cholera toxin adjuvant used (Mutsch et al., 2004). The device technology is now owned by a Dutch vaccine company but to our knowledge is not currently used in any marketed products. The single- and duo-dose devices mentioned above consist of a vial, a piston, and a swirl chamber. The spray is formed when the liquid is forced out through the swirl chamber.

These devices are held between the second and the third fingers with the thumb on the actuator. A pressure point mechanism incorporated in some devices secures reproducibility of the actuation force and emitted plume characteristics (Wermeling et al., 2005). Currently, marketed nasal migraine drugs like Imitrex and Zomig and the marketed influenza vaccine Flu Mist are delivered with this type of device (Wermeling et al., 2005). With sterile filling, the use of preservatives is not required, but overfill is required resulting in a waste fraction similar to the metered-dose, multi-dose sprays. To emit 100 μl, a volume of 125 μl is filled in the device (Pfeiffer/Aptar single-dose device) used for the intranasal migraine medications Imitrex (sumatriptan) and Zomig (zolmitriptan) and about half of that for a duo-dose design (Wermeling et al., 2005).

Nasal pressurized metered-dose inhalers (pMDIs):
Most drugs intended for local nasal action are delivered by spray pumps, but some have also been delivered as nasal aerosols produced by pMDIs. Following the ban on ozonedepleting chlorofluorocarbon (CFC) propellants, the number of pMDI products for both pulmonary and nasal delivery diminished rapidly, and they were removed from the US market in 2003 (Hankin et al., 2012). The use of the old CFC pMDIs for nasal products was limited due to complaints of nasal irritation and dryness. The particles from a pMDI are released at a high speed and the expansion of a compressed gas, which causes an uncomfortable "cold Freon effect" (Mygind and Vesterhauge1978). The particles emitted from the traditional pMDIs had a particle velocity much higher than a spray pump (5,200 vs. 1,500 cm/s at a distance 1–2 cm from the actuator tip) (Vidgren and Kublik, 1998). The issues related to the high particle speed and "cold Freon effect" have been reduced with the recently introduced hydrofluoroalkane (HFA)-based pMDI for nasal use offering lower particle speeds (Hankin et al., 2012). Recently, the first nasal pMDI using HFA as propellant to deliver the first generation topical steroid beclomethasone dipropionate (BDP) was approved for allergic rhinitis in the USA (Meltzer et al., 2012). Like spray pumps, nasal pMDIs produce a localized deposition on the anterior non-ciliated epithelium of the nasal vestibule and in the anterior parts of the narrow nasal valve, but due to quick evaporation of the spray delivered with a pMDI, noticeable "drip-out" may be less of an issue (Newman et al., 1987).

6.2. Performance parameters:
It should be clear that the parameters discussed below depend on the experimental conditions and the equipment used for the characterization. So it is important to use well controlled conditions (e.g. automated actuation at defined speed or force) and procedures for the measurement of performance parameters. From experience it can be told, that the combination of a particular spray pump with a formulation will result in a quite unique performance profile which is hard to meet when considering the use of another pump. The US-FDA recognized that and recommends for generic nasal sprays to use the same brand and model of devices (particularly the metering valve or pump and the actuator) as used in the reference product to get equivalence on the basis of in vitro tests (FDA Guidance for Industry, 2003).

Spray pattern:
The spray pattern is best described as a horizontal cut through the spray plume at a defined distance from the orifice, in most cases set at 30 mm. Various studies have found droplet size distributions of aqueous nasal spray products to have mass mean (median) diameter values between 44 and 62 m. These studies showed that the majority of the dose was deposited locally in the anterior one-third of the nose. The relationship between retention time and viscosity has shown that the addition of various concentrations of methylcellulose (MC) to a metered spray pump containing desmopressin resulted in a dose-related increase in mean particle size from 51 m (0 percent MC) to 81 m (0.25 percent MC) to 200 m (0.5 percent MC), without a change in mean spray weight. The longest retention time was observed for the 0.25 percent MC solution, which was attributed to its particle size (81 m) and not to an increase in viscosity, since a decrease in retention time was observed for the highest viscosity (0.5 percent MC) solution (Bond et al., 1984; Newman et al., 1987)

Particle-size distribution:
The nose is a very effective filter and most particles and droplets will be caught within the nasal cavity. Only particles less than 10 μm median aerodynamic diameter, so called fine particles, can reach the lower airways during nasal breathing. Most spray pumps will generate an aerosol with a mean particle size in the range of 20-100 μm which are recognized as fine mist and will deposit well in the nasal cavity. During the formation and dissipation phases much larger droplets (>300 μm) can be formed. Droplet size distribution for nasal sprays is assessed by laser diffraction methods. Results are typically expressed as a size in microns below which 10%, 50% or 90% of the volume of material exist and percentage of droplets less than 10 μm. Although a wide range of particles will certainly deposit in the nose, authorities require their characterization because it is a sensitive parameter to detect changes in pump quality or in the formulation.

Actuation force:
Nasal spray pumps are normally actuated by a fast movement of thumb, index and middle finger. More recently also pumps with side actuation became available. When actuated, the pumps should deliver the whole dose as fine mist within a fraction of a second. Actuation forces should be in the range of 30-80 N (~3-8 kg). As a rule of thumb, higher viscosity will require higher actuation force. Of course there is also a great impact coming from the device side. Geometry of the metering chamber, design of the valve mechanisms, internal friction, spring forces, dimensions of the swirling chamber have a great influence on this parameter. Some of them can be adapted by the manufacturer to a certain degree to meet the requirements of a particular formulation. Beside this, it is always recommended to test several pump types with a new formulation to find the best match and to meet requirements of the target group (children, elderly) (Suman et al., 2002).



Figure- 6: Nasal spray pumps.
In figure- 6, Standard nasal spray pumps on the left: This pump is actuated by pressing the actuator in a longitudinal movement towards the bottle. On the right side a nasal spray pump (Latitude®) designed for lateral actuation with the thumb which is preferred by some people.

Shot weight and delivered dose:
The volume of the metering chamber will define the delivered dose for a primed pump. This works normally fine for water or saline when the right actuation parameters (force, stroke acceleration) are used. Depending on surface tension and viscosity of the product, air may be trapped in the dosing chamber influencing priming and dose accuracy. Similar problems may occur when air bubbles come into the dip tube. Also too low actuation forces may lead to partial metering. To overcome the problem of partial metering, so called "userindependent" spray pumps were developed but are not widely used by the industry yet (Suman et al., 2002).

Pump Priming:
This is tested by reference to the number of shots required to initially prime the pump, and the loss of prime during a typical user test (i.e., the pump should not require repriming during normal daily use). If the product is only used intermittently, then repriming may be required.
Cap Removal Torque :
This test is designed to measure the potential for leakage during product life. Cap on- and off torques are measured at zero time and also during the period of the stability testing programme.

Bottles:
Bottles or containers are an integral part of drug delivery devices and will also influence the general appearance of the final product. Special shapes may be used to differentiate a product from competitors. Glass bottles are less prone to cause interactions and will give good protection to the formulation even during long storage intervals. Sometimes the glass can influence the stability of the formulation (change in pH, release of trace metals). This depends of course on the quality of the glass which is described by its hydrolytic class (hydrolytic class I-III is normally used for pharmaceutical products). The disadvantages which glass bottles may have are the higher weight and the risk to break when dropped. Bottles made of plastic material (e.g. polyethylene, polypropylene, PET) are sometimes used for nasal sprays but are mandatory for ophthalmic droppers because squeezing the bottles is needed to dispense the product. Pump supplier will most likely not manufacture these bottles themselves because a complete different technology is used. Parts for spray pumps or droppers are quite exclusively made by injection molding which gives high precision. Plastic bottle manufacturers use a process called blow-molding. The general principle is to make a hollow raw part and then blowing up the material to the final dimensions. The most important disadvantage for all bottles made of plastic material is evaporation/weight loss. Plastic materials are not a perfect barrier for gas or water evaporation. This problem can be tackled using laminated materials but these are more expensive. Another potential risk has to be considered: inks and adhesives from labels may migrate through the bottle wall and leach into the formulation (Marx et al., 2011).


7. REGULATORY ASPECTS
A "Guidance for Industry" document in draft form was issued by the FDA during 1999,
Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products: Chemistry, Manufacturing and Controls Documentation (FDA, 1999).
This document provides a plethora of information on issues the FDA will consider in submitted documentation supporting the approval of nasal products. There are over 1,600 lines in the document, and industry comments have been invited. Whilst the final document has yet to be issued, the draft is still an important reference. A brief review of the content of this draft document follows:

It is stated that nasal sprays have unique characteristics with respect to formulation, container closure system, manufacturing, in-process and final controls and stability. The product must deliver reproducible doses during the whole life of the product. Excipient controls are discussed in the FDA draft guidance; in many respects, the chemistry, manufacturing and controls (CMC) standards expected of excipients are starting to approach those required of the active pharmaceutical ingredient (API).

Test parameters are discussed in the FDA draft guidance. These include appearance, colour, clarity, identification, drug content (assay), impurities and degradation products and preservatives and stabilising excipients assay. For the device, the parameters include pump delivery; spray content uniformity through container life, spray pattern and plume geometry, droplet size distribution, particle size distribution (suspensions), microscopic evaluation (suspensions), foreign particles, microbial limits, preservative effectiveness, net content and weight loss (stability), leachables (stability), pH and osmolality.

The section on the container closure system is an important area for the FDA. They comment: The clinical efficacy of nasal and inhalation spray drug products is directly dependent on the design, reproducibility, and performance characteristics of the container closure system.

Also mentioned is the selection of a pump suitable for the formulation, and compatibility of the pump, container, and closure with formulation components, should be thoroughly investigated and established before initiating critical clinical, bioequivalence, and primary stability studies. Thus, it is no longer acceptable for the formulator to delay this compatibility testing until later in the development programme.
The key message is for the formulator to test early and ensure equivalence of the whole product throughout the development cycle. Leachables are specifically mentioned; data on their identity and concentration in the product and placebo are required through the shelf life and also under accelerated stability test conditions. Information should be submitted on source, chemical composition and physical dimensions of the container closure system, together with control and routine extraction tests. Acceptance criteria are also required.

The section on drug product stability provides clear guidance for the formulator. Considerations are the content of the stability protocol, test parameters, acceptance criteria and procedures, test intervals (long term, accelerated, intermediate), container storage (upright, inverted, horizontal) and test storage conditions (40°C/75 percent RH, 30°C/60 percent RH, 25°C/60 percent RH). For products packaged in semipermeable containers, the storage conditions are 40°C/15 percent RH, 30°C/40 percent RH and 25°C/40 percent RH; the reason for this is to provide a challenging environment to test the moisture permeability of the container. Moisture vapour loss will change the concentrations of all formulation ingredients (and hence the delivered dose), and may even result in precipitation of the active ingredient. The FDA re-quires stability data from three batches as the minimum to evaluate batch-to-batch variability, and also requires the expiry date to be based on data from full shelf-life stability studies of at least three batches of drug product (Day, 2004).

Another section states that drug product characterisation studies are required to "characterise the optimum performance properties of the drug product and to support appropriate labelling statements". These include studies on priming and repriming of the pump in various orientations, and studies on non-use after different periods. Also, the number of sprays required to prime the device should be determined. Resting time and temperature cycling are also discussed. In summary, it is apparent there are no short-cuts to attaining regulatory approval. A formulator who dismisses the requirements of the draft guidelines without strong scientific justification will give the FDA an unequivocal opportunity to delay the approval whilst the outstanding questions are answered (Day, 2004).


8. NASAL DFELIVERY OF PEPTIDES AND PROTEINS
A drug delivery route that is less technologically demanding than pulmonary delivery is nasal delivery. By virtue of relatively rapid drug absorption, possible bypassing of presystemic clearance and relative ease of administration, delivery of drug by the nasal route offers an attractive alternative for administering systemically active drugs. Simple nasal drops or a nasal spray, nasal gel can be used, and for particulate nasal delivery the particle size is not as important. A special aspect of nasal delivery is the possibility of achieving delivery transsynaptically directly into the brain using nanoparticles (Sharma, 2006). The nasal epithelium suited for permeation has an area of approximately 150 cm2, and this will limit the dose range given by this route. Higher bio-availabilities can be obtained with more advanced delivery systems, especially by adding enhancers that modulate the permeability of the epithelium (Chien et al., 1989; Anik et al., 1985).

Pharmaceutical drugs as well as endogenous hormones such as luteinizing-hormone-releasing hormone LHRH, thyrotropin-releasing hormone (TRH), vasopressin, calcitonin, oxytocin, ACTH, glucagon, insulin, interferons, and enkephalins, have been shown to be absorbed nasally in animal and human. The studies of the nasal delivery of a number of peptide-based pharmaceuticals demonstrated that systemic bioavailability can be improved by nasal route (Malcolmson and Embleton, 1998). For hydrophilic peptide and protein which furthermore can be degraded in the nasal cavity by peptidase and absorption considerably smaller for peptide calcitonin and insulin bioavailability of the order less than 1% has been reported (Schnurch and Scholler, 2000). In order to overcome the barrier to nasal absorption of these molecules, two main approaches have been utilized, modification of permeability of nasal membrane by employment of absorption enhancer, such as surfactants, bile salts, cyclodextrins, phospholipids, and fatty acids, and use of the mucoadhesive system such as bioadhesive, liquid formulation (e.g. chitosan) microsphere powder and liquid gelling, formulation that decreases the mucociliary clearance of the drug formulation and thereby increase contact time between the drug and site of the absorption (Anik et al.,1985).
Penetration enhancers are often used to improve peptide bioavailability in nasal formulations. A variety of different enhancers have been tried, and they work by one or several combined mechanisms. Some act by increasing the membrane fluidity and reducing the viscosity of the mucus layer, thereby increasing membrane permeability. Others act by transient loosening of the tight junctions between epithelial cells. The types of penetration enhancers discussed in the research literature include the following.
Bile salts (sodium glycocholate, deoxycholate, cholate)
Surfactants (polyoxyethylene lauryl ether-[laureth-9])
Chelating agents (ethylenediaminetetraacetic acid [EDTA], salicylates)
Fatty acids (sodium caprylate, laurate, caprate, oleic acid, monoolein)
Glycosides (saponin)
Glycyrrhetinic acid derivatives (sodium and dipotassium glycyrrhetinates)
Fusidic acid derivatives (sodium taurodihydrofusidate, sodium dihydrofusidate)
Phospholipids (lysophosphatidylcholine and palmitoyl and stearoyl derivatives)

(Donovan et al., 1990; Yamamoto et al., 1993). Of these penetration enhancers, the steroidal surfactants have been the subject of most study and have been examined in clinical trials. However, in most cases, there are adverse reactions of a stinging or burning sensation, discomfort, or a certain degree of pain, indicative of irritation potential. In experimental studies, the use of penetration enhancers is often accompanied by pathohistological changes to the nasal mucosa (Chandler et al., 1991). One reason for poor absorption by the nasal route may be the rapid removal of the drug from the site of absorption by mucociliary clearance (Dondeti et al. 1996; Quraishi et al., 1997). Bioadhesive gels adhere to the mucous and can reduce clearance and improve bioavailability. Microcrystalline cellulose, hydroxypropyl cellulose and neutralised Carbopol 934 have all shown different degrees of enhancement of nasal absorption of insulin in dogs. Bioadhesive starch microspheres have also shown enhanced absorption of desmopressin in sheep (Critchley et al., 1994). Gamma scintigraphy has been used to study microsphere clearance in man, and great differences have been observed. Starch microspheres have been used for nasal delivery of insulin in the rat with a bioavailability of about 30 percent (Edman and Bjork, 1988). The use of cyclodextrins to improve the nasal absorption of insulin has been demonstrated in rats (Merkus et al., 1991). Combinations of an absorption enhancer and a bioadhesive agent have been shown to provide a synergistic improvement in bioavailability (Dondeti et al., 1996).
9. CONCLUSION
Nasal drug delivery system is a promising alternative route of administration for the several systemically acting drugs with poor bioavailability and it has advantages in terms of improved patient acceptability and compliance compared to parenteral administration of drugs. This delivery system is beneficial in conditions like Parkinson s disease, Alzheimer s disease or pain because it requires rapid and/or specific targeting of drugs to the brain and it is a suitable route to produce immune response against various diseases like anthrax, influenza etc., by delivering the vaccines through the nasal mucosa. In the near future, let us hope that intranasal products most probably comprise for crisis treatments, such as erectile dysfunction, sleep induction, acute pain (migraine), panic attacks, nausea, heart attacks and Parkinson s disease and novel nasal products for treatment of long-term illnesses, such as diabetes, growth deficiency, osteoporosis, fertility treatment and endometriosis will also be marketed. The successful application of these attributes requires careful design of characteristics of both the drug formulation and delivery device, and a clear understanding of the ways in which they impact on each other.

















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