discussion about narial drug delivery

www.wjpr.net Vol 7, Issue 17, 2018.

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Sharma. World Journal of Pharmaceutical Research

DISCUSSION ABOUT NARIAL DRUG DELIVERY

*Sneha Sharma

India.

ABSTRACT

Interest in intranasal (IN) or intranarial administration as a non-

invasive route for drug delivery continues to grow rapidly. The nasal

mucosa offers numerous benefits as a target issue for drug delivery,

such as a large surface area for delivery, rapid drug onset, potential for

central nervous system delivery, and no first-pass metabolism. A wide

variety of therapeutic compounds can be delivered IN, including

relatively large molecules such as peptides and proteins, particularly in

the presence of permeation enhancers. The current review provides in-

depth discussion of anatomy and physiology of nose, advantages and limitations of nasal

route, various factors affecting nasal formulations and barrier to nasal cavity, and various

nasal formulations. It is anticipated that the present review will prove useful for considering

IN delivery as a delivery route.

INTRODUCTION

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 compounds 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.[1]

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”.[2]

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 mechanisam.[3]

World Journal of Pharmaceutical Research SJIF Impact Factor 8.074

Volume 7, Issue 17, 1389-1405. Review Article ISSN 2277– 7105

Article Received on

14 August 2018,

Revised on 05 Sept. 2018,

Accepted on 26 Sept. 2018,

DOI: 10.20959/wjpr201817-13465

*Corresponding Author

Sneha Sharma

India.


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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. It has been do-

cumented that nasal administration of certain- hormones and steroids have resulted in a more

complete absorption.[4]

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 administration includes the treatment of congestion, rhinitis, sinusitis and related

allergic or chronic conditions, and has resulted in a variety of different medications in-

cluding corticoids, antihistamines, anticholinergic and vasoconstrictors. In recent years,

increasing investigations of the nasal route have focused especially on nasal application for

systemic drug delivery.[5]

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, nocturnalenuresis 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.

This review article provides a brief overview of the advantages and limitations of nasal drug

delivery system and anatomy of nasal cavity, mechanism of nasal absorption, barriers to nasal

absorption, nasal drug delivery formulation and applications of nasal drug delivery systems.

PHYSIOLOGY OF THE NASAL CAVITY

The major functions of the nasal cavity are breathing and smelling i.e. olfaction.[6]

Nasal

cavity is lined with mucus layer and hairs which are involved in the humidification of the air

functions, trapping inhaled particles and pathogens. The other functions include the

resonance of produced sounds, mucociliary clearance and immunological activities.[7-8]

Anatomically, human nasal cavity fills the space between the base of the skull and the roof of

the mouth; above, it is supported by the ethmoid bones and, laterally, by the ethmoid,

maxillary and inferior conchae bones.[9]

The human nasal cavity has a total volume of 15- 20


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mL and a total surface area of approximately 150 cm2.[10]

It is divided by nasal septum into

two symmetrical halves, each one opening at the face through nostrils and extending posterior

to the nasopharynx. Both symmetrical halves consist of four areas;

·Nasal vestibule

·Atrium

·Respiratory region

·Olfactory region

Nasal vestibule

The anterior part of the nasal cavity is called the vestibule present just inside the nostrils, with

a surface area of about 0.6 cm2.[11]

It comprises of nasal hairs called vibrissae, which filter the

inhaled particles. It is covered by a stratified squamous and keratinized epithelium with

sebaceous glands.[11]

It offers a high resistance against toxic substances. Absorption of drugs

through this region is very difficult.

Atrium[12]

It is the intermediate area between nasal vestibule and respiratory region. Its anterior section

is made up of stratified squamous epithelium and the posterior area by pseudostratified

columnar cells with microvilli.

Respiratory region[12]

The nasal respiratory region is also called conchae, is the largest part of the nasal cavity and

is divided into the superior, middle and inferior turbinates responsible for temperature

regulation of inhaled air. Between them there are spaces, called meatus. The nasal respiratory

mucosa, is the most important section for delivering drugs systemically, is composed of

epithelium, basement membrane and lamina propria. The nasal respiratory epithelium

consists of pseudostratified columnar epithelial cells, globet cells, basal cells and mucous and

serous glands.[7]

Many of the epithelial cells are covered with microvilli. The microvilli

enhance the respiratory surface area, nasal epithelium is covered with a thin mucus layer

produced by secretory glands and goblet cells. These secrete mucin. Nasal mucus layer

consists of 95% of water, 2.5-3% of mucin, and 2% of electrolytes, proteins, lipids, enzymes,

antibodies, sloughed epithelial cells and bacterial products. The mucin in the nasal mucus

layer may trap large molecular weight drugs, such as peptides and proteins.


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Olfactory region

The olfactory region is located in the roof of the nasal cavity and extends a short way down

the septum.[11]

Its neuro epithelium is the only part of the CNS that is directly exposed to the

external environment.[19]

The olfactory epitheium is pseudostratified but contains specialized

olfactory receptor cells important for smell perception.[11,19]

Figure 1: Anatomy and histology of human nasal cavity.

Transport pathways from nose to brain[13]

The different routes by which a drug delivered nasally can reach the CSF(cerebro spinal

fluid) and the brain are shown schematically in Fig. 2 where the thickness of the arrows

indicates the likelihood of drugs exploiting the route in question. When drugs are

administered nasally the drug will normally be rapidly cleared by the mucociliary clearance

system Some of the drug (for lipophilic drugs up to 100% but normally much less) will be

absorbed into the bloodstream from where it reaches the systemic circulation directly and

subsequently is eliminated from the blood stream via normal clearance mechanisms The drug


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can reach the brain from the blood by crossing the blood–brain barrier (the so-called systemic

pathway to the brain) but can also be eliminated from the CSF into the blood. Drug can also

be absorbed from the nose via the olfactory region into the CSF and possibly further into the

brain. The amount of drug absorbed or lost via the different pathways has been shown to be

highly dependent upon the characteristics of the drug, especially liphophilicity and molecular

weight, but also the drug formulation.

Figure 2: The nose to brain transport route.

Advantages of Nasal Drug Delivery System[14-16]

1. Drug degradation that is observed in the gastrointestinal tract is absent.

2. Hepatic first – pass metabolism is absent.

3. Rapid drug absorption and quick onset of action can be achieved.

4. The bioavailability of larger drug molecules can be improved by means of absorption

enhancer or other approach.

5. The nasal bioavailability for smaller drug molecules is good.

6. Drugs that are orally not absorbed can be delivered to the systemic circulation by nasal

drug delivery.

7. Studies so far carried out indicate that the nasal route is an alternate to parenteral route,

especially, for protein and peptide drugs.

8. Convenient for the patients, especially for those on long term therapy, when compared

with parenteral medication.

9. Large nasal mucosal surface area for dose absorption


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10. Rapid drug absorption via highly-vascularized mucosa

11. Rapid onset of action

12. Ease of administration, non-invasive

13. Avoidance of the gastrointestinal tract and first-pass metabolism

14. Improved bioavailability

15. Lower dose/reduced side effects

16. Minimal aftertaste

17. Improved convenience and compliance

18. Self-administration

19. New patent coverage for drug formulations about to expire

LIMITATIONS

1. The histological toxicity of absorption enhancers used in nasal drug delivery system is not

yet clearly established.

2. Relatively inconvenient to patients when compared to oral delivery systems since there is a

possibility of nasal irritation.

3. Nasal cavity provides smaller absorption surface area when compared to GIT.

MECHANISM OF DRUG ABSORPTION THROUGH NARIAL MUCOSA[15-18]

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. Large or charged particles may

however, find it more difficult to cross. Mucin, the principle protein in the mucus, has the

potential to bind to solutes, hindering diffusion. Additionally, structural changes in the mucus

layer are possible as a result of environmental changes, such as pH or temperature.[17]

Subsequent to a drugs passage through the mucus, there are several mechanisms for

absorption through the mucosa.[18]

These include transcellular or simple diffusion across the membrane, paracellular transport

via movement between cell and transcytosis by vesicle carriers.[17]

Obstacles to drug

absorption include potential metabolism before reaching systemic circulation and limited

residence time in the cavity. Several mechanisms have been proposed but the following two

mechanisms have been considered predominantly.

1. 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


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between intranasal absorption and the molecular weight of water-soluble compounds. Poor

bioavailability was observed for drug with a molecular weight greater than 1000 Daltons.

2. The second mechanism involves transport through a lipoidal route is also known as the

transcellular process and is responsible for the transport of lipophilic drugs that show a rate

dependency on their lipophilicity

3. Drug also cross cell membranes by an active transport route via carrier-mediated means or

transport through the opening of tight junctions. For examples, chitosan, a natural biopolymer

from shellfish, opens tight junctions between epithelial cells to facilitate drug transport.

Figure 2: (A1) Intercellular spaces, (A2) Tight junctions,(B1) Passive diffusion, (B2)

Active transport, (C) Transcytosis.

FACTORS AFFECTING THE CHARACTERISTICS OF NARIAL DRUG

DELIVERY[18-21]

1. PHYSICOCHEMICAL PROPERTIES OF DRUGS

i. Chemical form

The chemical form of a drug is important in determining absorption. For example, conversion

of the drug into a salt or ester form can also alter its absorption.

Huang et al (1985) studied the effect of structural modification of drug on absorption.[19]

It

was observed that in-situ nasal absorption of carboxylic acid esters of L-Tyrosine was

significantly greater than that of L-Tyrosine.


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ii. Polymorphism

Polymorphism is known to affect the dissolution rate and solubility of drugs and thus their

absorption through biological membranes.

iii. Molecular weight

A linear inverse correlation has been reported between the absorption of drugs and molecular

weight up to 300 Da. Absorption decreases significantly if the molecular weight is greater

than 1000 Da except with the use of absorption enhancers. Shape is also important. Linear

molecules have lower absorption than cyclic – shaped molecules.

iv. Particle size

It has been reported that particle sizes greater than 10μm are deposited in the nasal cavity.

v. Solubility & dissolution rate

Drug solubility and dissolution rates are important factors in determining nasal absorption

from powders and suspensions. The particles deposited in the nasal cavity need to be

dissolved prior to absorption. If a drug remains as particles or is cleared away, no absorption

occurs.

2. FORMULATION FACTORS

i. 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:

maintain functionality of excipients such as preservatives, and

Lysozyme is found in nasal secretions, which is responsible for destroying certain bacteria at

acidic pH. Under alkaline conditions, lysozyme is inactivated and the nasal tissue is

susceptible to microbial infection. It is therefore advisable to keep the formulation at a pH of


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4.5 to 6.5, keeping in mind the physicochemical properties of the drug as drugs are absorbed

in the unionized form.

ii. 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.

iii. Osmolarity

Drug absorption can be affected by tonicity of formulation. Shrinkage of epithelial cells has

been observed in the presence of hypertonic solutions. Hypertonic saline solutions also

inhibit or cease ciliary activity. Low pH has a similar effect as that of a hypertonic solution.

iv. Gelling / Viscosity building agents or gel-forming carriers

Pennington et al (1988) demonstrated that increase in solution viscosity may provide a means

of prolonging the therapeutic effect of nasal preparations.[20]

Suzuki et al (1999) showed that

a drug carrier such as hydroxypropyl cellulose was effective in improving the absorption of

low molecular weight drugs but did not produce the same effect for high molecular weight

peptides.[21]

v. Solubilizers

Aqueous solubility of 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 can be used to

enhance the solubility of drugs.[43]

Other options include the use of surfactants or

cyclodextrins such as HP-β-cyclodextrin that serve as a biocompatible solubilizer and

stabilizer in combination with lipophilic absorption enhancers.

vi. Preservatives

Most nasal formulations are aqueous based and need preservatives to prevent microbial

growth. Parabens, benzalkonium chloride, phenyl ethyl alcohol, EDTA and benzoyl alcohol

are some of the commonly used preservatives in nasal formulations. Van De Donk et al

(1980), showed that mercury containing preservatives have a fast and irreversible effect on

ciliary movement and should not be used in nasal systems.[44]


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vii. Antioxidants

Usually, antioxidants do not affect drug absorption or cause nasal irritation. Commonly used

antioxidants are sodium metabisulfite, sodium bisulfite, butylated hydroxyl toluene and

tocopherol.

viii. Humectants

Many allergic and chronic diseases are often connected with crusts and drying of mucous

membrane. Therefore humectants can be added especially in gel-based nasal products.

Humectants avoid nasal irritation and are not likely to affect drug absorption. Common

examples include glycerin, sorbitol and mannitol.

ix. Drug concentration, dose & dose volume

Drug concentration, dose and volume of administration are three interrelated parameters that

impact the performance of the nasal delivery performance. Nasal absorption of L-Tyrosine

was shown to increase with drug concentration in nasal perfusion experiments.

x. Role of absorption enhancers

Absorption enhancers may be required when a drug exhibits poor membrane permeability,

large molecular size, lack of lipophilicity and enzymatic degradation by amino peptidases.

Osmolarity and pH may accelerate the enhancing effect. Absorption enhancers improve

absorption through many different mechanisms, such as increasing membrane fluidity,

increasing nasal blood flow, decreasing mucus viscosity, and enzyme inhibition.

3. PHYSIOLOGICAL FACTORS

i. Effect of deposition on absorption

Deposition of the formulation in the anterior portion of the nose provides a longer nasal

residence time. The anterior portion of the nose is an area of low permeability, while

posterior portion of the nose is where the drug permeability is generally higher, and provides

shorter residence time.

ii. Nasal blood flow

Nasal mucosal membrane is very rich in vasculature and plays a vital role in the thermal

regulation and humidification of the inhaled air. The blood flow and therefore the drug

absorption will depend upon the vasoconstriction and vasodilatation of the blood vessels.


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iii. 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. The level of amino-peptidase present is much lower than

that in the gastrointestinal tract. Peptides may also form complexes with immunoglobulin

(Igs) in the nasal cavity leading to an increase in the molecular weight and a reduction of

permeability.

iv. Effect of mucociliary clearance[45, 46]

The absorption of drugs is influenced by the residence (contact) 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 pathological condition

Intranasal pathologies may affect the nasal mucociliary transport process and/or capacity for

nasal absorption.

Barriers for Narial drug absorption[22-24]

Mucociliary clearance

Particles entrapped in the mucus layer are transported with it and thereby effectively cleared

from the nasal cavity. The combined action of the mucus layer and cilia is called mucociliary

clearance. This is an important, non-specific physiological defence mechanism of the

respiratory tract to protectagainst noxious inhaled materials. Mucus traps the particles of dust,

bacteria and drug substances and is transported towards the nasopharynx at a speed of 5 - 8

mm/min, where it is swallowed. The normal mucociliary transit time in humans has been

reported to be 12 to 15 min.[22]

Protective barriers

The first step in the absorption of drugs from the nasal cavity passed through the mucus.

Uncharged substances with small molecular weight can easily pass through this layer.

However, larger or charged particles may find it more difficult to cross. Mucin, the principal

protein in the mucus, has the potential to bind to solutes, hindering diffusion. Additionally,

structural changes in the mucus layer are possible as a result of environmental changes such

as pH, temperature etc. The nasal membrane is a physical barrier and the mucociliary

clearance is a temporal barrier to drug absorption across the nasal epithelium.


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Enzymatic barrier

The role of the enzymatic barrier is to protect the lower respiratory airways from toxic

agents; the nasal mucosa contains many enzymes such as cytochrome P450 dependent

monooxygenase, carboxyl esterase and aminopeptidase. Although nasal delivery avoids

hepatic first-pass metabolism to some extent, the nasal mucosa provides a pseudo-first-pass

effect. In addition, there are various barriers in the nasal membrane for protection from the

microorganisms, allergens and irritating substances from the environment that must be

overcome by drugs before they can be absorbed into the systemic circulation.[24]

Strategies for Narial drug delivery

1. Nasal spray[80,81]

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

from 25 to 200 μm. The particle size and morphology (for suspensions) of the drug and

viscosity of the formulation determine the choice of pump and actuator assembly.

2. Nasal drops

Nasal drops are one of the most simple and convenient systems developed for nasal delivery.

The main disadvantage of this system is the lack of the dose precision and therefore nasal

drops may not be suitable for prescription products. It has been reported that nasal drops

deposit human serum albumin in the nostrils more efficiently than nasal sprays.

3. Nasal gels[25]

Nasal gels are high-viscosity thickened solutions or suspensions. The advantages of a nasal

gel includes the reduction of post-nasal drip due to high viscosity, reduction of taste impact

due to reduced swallowing, reduction of anterior leakage of the formulation, reduction of

irritation by using soothing/emollient excipients and target to mucosa for better absorption.

4. Nasal powder[25]

This dosage form may be developed if solution and suspension dosage forms cannot be

developed e.g., due to lack of drug stability. The advantages to the nasal powder dosage form

are the absence of preservative and superior stability of the formulation. However, the

suitability of the powder formulation is dependent on the solubility, particles size,

aerodynamic properties and nasal irritancy of the active drug and /or excipients.


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5. Liposomes[26,27]

Liposomes are phospholipids vesicles composed by lipid bilayers enclosing one or more

aqueous compartments and wherein drugs and other substances can be included. Liposomal

drug delivery systems present various advantages such as the effective encapsulation of small

and large molecules with a wide range of hydrophilicity and pKa values. In fact, they have

been found to enhance nasal absorption of peptides such as insulin and calcitonin by

increasing their membrane penetration. This has been attributed to the increasing nasal

retention of peptides, protection of the entrapped peptides from enzymatic degradation and

mucosal membrane disruption Jain et al. incorporated insulin in liposomes coated with

chitosan and carbapol and administered them intranasally to rats. The results demonstrated

that this formulation was effective and that its mucoadhesive property is a viable option for a

sustained release of insulin. Moreover, liposomal drug delivery systems were also reported as

useful for influenza vaccine and non-peptide drugs such as nifedipine. Liposomes can be

incorporated in different formulations. For example, Ding et al. obtained a rapid onset of

action and sustained delivery of levonorgestrel when it was intranasally administered as a

liposome suspension. Furthermore, positive results were also found during nasal delivery of

acyclovir in a liposomal gel. The use of a liposomal gel not only promoted the prolonged

contact between the drug and the absorptive site, but also facilitated direct absorption through

the nasal mucosa.

6. Nanoparticles

Nanoparticles may offer several advantages due to their small size, but only the smallest

nanoparticles penetrate the mucosal membrane by paracellular route and in a limited quantity

because the tight junctions are in the order of 3.9-8.4 Å. Controversial results are found when

using nanoparticles in intranasal drug delivery.

In fact, there are few publications wherein nanoparticle formulations do not significantly

enhance the drug transport across the nasal cavity. The low bioavailability obtained can be

due to the fact that particles are probably taken up by M-cells in the nasal associated

lymphoid tissue and, therefore, transported into the lymphatic system and blood stream. In

contrast, other studies have suggested that nanoparticle systems may be ideally suited for the

delivery of nasal vaccines.


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7. Intranasal Microspheres[28]

Microsphere technology has been widely applied in designing formulations for nasal drug

delivery. Microspheres are usually based on mucoadhesive polymers (chitosan, alginate),

which present advantages for intranasal drug delivery. Furthermore, microspheres may also

protect the drug from enzymatic metabolism and sustain drug release, prolonging its effect.

Wang et al., have investigated laminated gelatin microspheres as a nasal drug delivery system

for insulin. They have observed a significant hypoglycemic effect when administered

intranasally in dry powder form to rats, but no significant effect was achieved when given in

a suspension. Gavine et al., have analyzed nasal mucosa after its exposure to microspheres of

alginate/chitosan containing metoclopramide. They observed open tight junctions in the

epithelium and also stated that these spray- dried microspheres have promising properties as

mucoadhesive nasal carriers.

8. Nasal Inserts

Nasal inserts are novel, bioadhesive, solid dosage forms for prolonged systemic drug delivery

via the nasal route. The principle of the dosage form is to imbibe nasal fluid from the mucosa

after administration and to form a gel in the nasal cavity to avoid foreign body sensation. This

gel adheres to the nasal mucosa due to its bioadhesive properties. In addition, it acts as

release controlling matrix, thus allowing sustained drug delivery. Due to dissolution of the

gel and / or mucociliary removal towards the nasopharynx, there is no need to remove

the insert mechanically after it is depleted of drug.

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discussion about narial drug delivery

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