05 Nasal Drug Delivery

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Nasal Drug Delivery Systems

The nasal administration of medicines for the symptomatic relief and prevention or treatment of topical nasal conditions has been widely used for a long period of time e.g. in the Ayurvedic system of Indian medicine.

Recently, the nasal mucosa has seriously emerged as a therapeutically viable route for the systemic drug delivery.

In general, among the primary targets for intranasal administration are pharmacologically active compounds with poor stability in gastrointestinal fluids, poor intestinal absorption and/or extensive hepatic first-pass elimination, such as peptides, proteins and polar drugs

Advantages Of Nasal Drug Delivery Systems

1. Patient compliance:

Easy accessibility and needle free painless drug application without the necessity of trained personnel, facilitates self-medication, thus improving patient compliances compared to parenteral routes.

2. Higher bioavailability:

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

3. Avoidance of GI conditions:

Avoids the harsh environmental conditions in the gastrointestinal tract (chemical and enzymatic degradation of drugs)

4. Avoidance of first pass metabolism:

Avoids of hepatic first pass metabolism and thus potential for dose reduction compared to oral delivery.

5. Alternative to parenteral administration:

Rapid absorption and fast onset of action due to relatively large absorption surface and high vascularization. So nasal administration of suitable drug would therefore be effective in emergency therapy as an alternative to parenteral administration routes.

6. Direct delivery to CNS:

Potential for direct delivery of drug to the central nervous system via the olfactory region, thus bypassing the blood brain barrier.

7. Direct delivery of vaccine:

Direct delivery of vaccines to lymphatic tissue and induction of a secretary immune response at distant mucosal site.

Limitations

Once administered, rapid removal of the therapeutic agent from the site of absorption is difficult. Pathologic conditions such as cold or allergies may alter significantly the nasal bioavailability.

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Physiological aspects of the nose

In humans and other animal species the major functions of the nasal cavity are breathing and olfaction.

Moreover, trapping inhaled particles and pathogens, resonance of produced sounds, mucociliary clearance (MMC), immunological activities and metabolism of endogenous substances are also essential functions of nasal structures.

The human nasal cavity has a total volume of 15-20 mL and a total surface area of approximately 150 cm2

It is divided by middle (or 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 and olfactory region

These are distinguished according to their anatomic and histological characteristics (Figure 1).



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1. Nasal vestibule:

Nasal vestibule is the most anterior part of the nasal cavity, just inside the nostrils, and presents an area about 0.6 cm2.

Here, there are nasal hairs, also called vibrissae, which filter the inhaled particles.

2. Atrium:

Atrium is the intermediate area between nasal vestibule and respiratory region.

3. Respiratory region:

The nasal respiratory region, also called conchae, is the largest part of the nasal cavity and it is divided in superior, middle and interior turbinates which are projected from the lateral wall.

These specialized structures are responsible for humidification and temperature regulation of inhaled air.


Figure 1: Anatomy and histology of human nasal cavity.


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4. Olfactory region:

The olfactory region is located in the roof of the nasal cavity and extends a short way down the septum and lateral wall. Its neuroepithelium is the only part of the CNS that is directly exposed to the external environment.

Mechanism Of Drug Absorption

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

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

These include:

Paracellular transport via movement between cell and transcytosis by vesicle carriers. Transcellular or simple diffusion across the membrane. The first mechanism involves an aqueous route of transport, which is also known as the paracellular

route. This route is slow and passive.

There is an inverse log-log correlation between intranasal absorption and the molecular weight of water soluble compounds. Poor bioavailability was observed for drugs with a molecular weight greater than 1000.

The second mechanism involves transport through a lipoidal route that is also known as the transcellular process and is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity.

Drugs also cross cell membranes by an active transport route via carrier mediated means or transport through the opening of tight junctions.

Factors Influencing Nasal Drug Absorption

A) Factors Related to Drug

a) Lipophilicity:

On increasing lipophilicity, the permeation of the compound normally increases through nasal mucosa. Although the nasal mucosa was found to have some hydrophilic character, it appears that these mucosa are primarily lipophilic in nature and the lipid domain plays an important role in the barrier function of these membranes.

Example: Lipophilic compounds alprenolol and propranolol were well absorbed from the nasal mucosa, in contrast to the hydrophilic drug metoprolol.

b) Chemical Form:



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The chemical form of a drug can be important in determining absorption. For example, conversion of the drug into a salt or ester form can alter its absorption.

Example: In-situ nasal absorption of carboxylic acid esters of L-Tyrosine was significantly greater than that of L-Tyrosine.

c) Molecular Weight:

It has been reported that nasal absorption falls off sharply for a drug molecule with a molecular weight of greater than 1000; oral absorption declines even more steeply when the molecular weight goes beyond 400.

d) Partition Coefficient and pKa:

As per the pH partition theory, unionized species are absorbed better compared with ionized species and the same holds true in the case of nasal absorption. The nasal absorption of weak electrolytes such as salicylic acid and aminopyrine was found to be highly dependent on their degree of ionization.

e) Effect of Perfusion Rate:

The increase in perfusion rate increases the nasal absorption initially and then it reaches in a plateau level that is independent on perfusion rate.

f) 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, no absorption takes place.

B) Factors Related to Formulation

a) pH and Mucosal Irritancy:

The pH of the formulation, as well as that of nasal surface, can affect a drug’s permeation. To avoid nasal irritation, the pH of the nasal formulation should be adjusted to 4.5–6.5.

b) Osmolarity:

The effect of osmolarity on the absorption of secretin found that, absorption reached a maximum at a sodium chloride concentration of 0.462 M; because shrinkage of the nasal epithelial mucosa.

c) Viscosity:

A higher viscosity of the formulation increases contact time between the drug and the nasal mucosa thereby increasing the time for permeation.

d) Pharmaceutical form:

Nasal drops are the simplest and the most convenient nasal pharmaceutical form, but the exact amount of drug delivered is not easily quantified and often results in overdose. Moreover, rapid nasal drainage can occur when using this dosage form.



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Solution and suspension sprays are preferred over powder sprays because the last one easily prompted the development of nasal mucosa irritation.

Recently, gel devices have been developed for a more accurate drug delivery.

Different Dosage Forms for Nasal Drug Delivery

The selection of dosage form depends upon the drug being used, proposed indication, patient population and last but not least, marketing preferences.

Some delivery systems and their important features are summarized below:

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 dose precision and therefore nasal drops may not be suitable for prescription products.

Nasal Sprays

Both solution and suspension formulations can be formulated into nasal sprays. Due to the availability of metered dose pumps and actuators, a nasal spray can deliver an exact dose from 25 to 200 L. The particle size and morphology (for suspensions) of the drug and viscosity of the formulation determine the choice of pump and actuator assembly.

Solution and suspension sprays are preferred over powder sprays because powder results in mucosal irritation.

Nasal Gels

Nasal gels are high viscosity thickened solutions or suspensions. The advantages of a nasal gel include:

The reduction of post nasal drip due to high viscosity Reduction of taste impact due to reduced swallowing Reduction of anterior leakage of the formulation Reduction of irritation by using soothing/emollient excipients Target delivery to mucosa for better absorption.


Nasal Drop

Nasal Spray


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Nasal Powders

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 forms are the absence of preservative and superior stability of the formulation.

However, the suitability of the powder formulation is dependent on the solubility, particle size, aerodynamic properties and nasal irritancy of the active drug and/or excipients.

Others:

Over the last years, specialized systems such as lipid emulsions, microspheres, liposomes and films have also been developed to improve nasal drug delivery.

Barriers For Nasal Drug Delivery

Mucociliary clearance:

The general fast clearance of the administered formulation from the nasal cavity due to the mucociliary clearance mechanism is an important factor for low membrane transport. This is especially the case when the drug is not absorbed rapidly enough across the nasal mucosa.

It has been shown that for both liquid and powder formulations, which are not bioadhesive, the half life for clearance is of the order of 15 - 30 min. The use of bioadhesive excipients in the formulations is an approach to overcome the rapid mucociliary clearance.

Low bioavailability:

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

Nasal absorption of such polar drugs can be greatly improved by co-administration of absorption enhancing agents. Agents generally used for transnasal absorption includes surfactants (laureth-9, sodium laurylsulfate), bile salts and bile salt derivatives (sodium glycocholate, sodium deoxycholate, sodium taurodihydrofusidate) etc.

Enzymatic Degradation:

Another contributing, but often less considered factor to the low bioavailability of peptides and proteins across the nasal mucosa is the possibility of an enzymatic degradation of the molecule in the lumen of the nasal cavity or during passage through the epithelial barrier.

Carboxyl esterases, aldehyde dehydrogenases, epoxide hydrolases and gluthatione S-transferases have been found in nasal epithelial cells and are responsible for the degradation of drugs in nasal mucosa



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Transporters and efflux systems:

Multidrug resistance transporters has already been identified in human nasal respiratory and olfactory mucosa, which may be involved in the transport of a wide variety of hydrophobic and amphiphilic drugs.

P-gp is an efflux transporter that exists in the apical area of ciliated epithelial cells and in the submucosal vessels of the human olfactory region.

The use of enzyme inhibitors and/or saturation of enzymes may be approaches to overcome this barrier

Enhancement of Nasal Absorption

Several methods have been used to facilitate the nasal absorption of drugs:

a) Structural modification: The chemical modification of the molecular structure of a drug has been often used to modify the physicochemical properties of a drug, and hence it could also be utilized to enhance the


Drug

Drug

P-glycoprotein

Extracellular Intracellular

ATP

ADP + Pi

P-glycoprotein, an ATP-dependent efflux pump, preventing the influx of a drug from nasal membrane to CNSEffl

uxInflux

Properties of the formulation

Mucoadhesive drug

Enzyme inhibitors

Absorption enhancersNovel formulation forms

Absorption(NDDS)

Characteristics of the drug

Physiological factors of nasal mucosa

Factors work in nasal drug delivery

Strategies to make the system potential for delivery


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nasal absorption of a drug.

b) Salt and ester formation: The drug could be converted to form a salt or an ester for achieving better transnasal permeability, such as formation of a salt with increased solubility or of an ester with better nasal membrane permeability.

c) Formulation design: Proper selection of formulation excipients could improve the stability and/or enhance the nasal absorption of drugs.

i) Absorption enhancers: Bile salts and derivatives e.g. Sodium deoxycholate, sodium glycocholate, sodium taurodihydrofusidate

Possible mechanisms:

Disrupting the membrane Opening the tight junction

Enzyme inhibition Mucolytic activity

ii) Chelating agents:Ethylene-diaminetetraacetic acid, salicylates.

d) Surfactants: Incorporation of surfactants into nasal formulations could modify the permeability of nasal mucosa, which may facilitate the nasal absorption of drugs. Example - Sodium lauryl sulphate, saponin, polyoxyethylene-9-lauryl ether.

e) Enzyme inhibitors: A contributing factor to the low bioavailability of peptides and proteins across the nasal mucosa is the possibility of an enzymatic degradation. Enzyme inhibitors lower the degradation and make the drugs more bioavailable. Example: Bestatin, amastatin.

f) Mucoadhesive or Bioadhesive materials: Carbopol, chitosan, starch, albumin, gelatin etc.

Application of Nasal Drug Delivery Systems

I. Delivery of Vaccines Through Nasal Route:

Nasal mucosa is extremely rich in specialized cells and houses organized lymphatic tissues involved in the first line defense against airborne microorganism.

Nasal delivery of vaccines has been reported to not only produce systemic immune response, but also local immune response in the nasal lining, providing additional barrier of protection. Mucosal sites have a potential as first line of defense against entering pathogens.

Main reasons for exploiting the nasal route for vaccine delivery:

The nasal mucosa is the first site of contacts with inhaled pathogens. The nasal passages are rich in lymphoid tissue. Creation of both mucosal and systemic immune responses. Low cost, patient friendly, non injectable and safe.

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



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II. Delivery of Drugs to Brain Through Nasal Cavity:

The nose to brain delivery would be beneficial in therapeutic situations where a rapid and/or specific targeting of drugs to the brain is required.

Conditions such as Parkinson’s disease, Alzheimer’s disease or pain would be benefited from the development of nasal delivery systems, which will increase the fraction of drug that reach the CNS after nasal delivery.

The olfactory region located at the upper remote parts of the nasal passages offers the potential for certain compounds to circumvent the blood-brain barrier and enter into the brain.


Nasal drug products for vaccination available in the market


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III. Delivery of Peptide and Non-Peptide Drugs Through Nasal Route for Systemic Effect:

Because of their physicochemical instability and susceptibility to hepato-gastrointestinal first pass elimination, peptide and protein pharmaceuticals have a generally low oral bioavailability and are normally administered by parenteral routes.

Most nasal formulations of peptide or protein pharmaceuticals have been simply prepared in simple aqueous (or saline) solution with preservatives.

The efficacy of a peptide or protein pharmaceutical delivered intranasally is highly dependent upon its molecular structure and molecular size.


Delivery of drug molecule to brain from Nose

Nasal Drug Products (Proteins and Peptides) for Systemic Drug Delivery


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Unlike high molecular weight peptides, the small non-peptide lipophilic drugs (MW below 1000) are better absorbed through the nasal mucosa even in the absence of absorption enhancers.

The underlying epithelium of the nasal membrane is highly vascularized and the nasal cavity has a large surface area readily accessible for drug absorption because of the presence of nasal turbinates.

As a consequence, low molecular weight lipophilic drugs, such as propranolol, progesterone are well absorbed across the nasal cavity.


Nasal Drug Products (Non-Peptide) for Systemic Drug Delivery


05 Nasal Drug Delivery

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