Nasal drug delivery system: An introduction, mechanism with its advantages.

What is the nasal drug delivery system?

Nasal-dosage-form
Nasal dosage form

Nasal route of administration from which the drugs are insufflated through the nose. This can be a form of either topical administration or systemic administration. Whereas the drugs thus locally delivered in a nasal dosage form that can go on to have either purely local or systemic effects. Nasal sprays are locally acting drugs in the form of decongestants for the treatment of cold and allergy, whose systemic effects are usually minimal. Examples of systemically active drugs in the form of nasal sprays are such as migraine drugs, nicotine replacement, and hormone treatments.

These are primarily suitable for potent drugs since only a limited volume can be sprayed into the nasal cavity. Drugs for sustained and frequent administration may be less applicable, because of the risk of harmful long-term effects on the nasal epithelium. These are also associated with high mutable in the number of drugs that absorbed.

Introduction-

The nasal drug delivery system is to deliver medications directly to the nasal cavity, where it can be absorbed directly by the appropriate tissues. It is proved that medications against some CNS disorders can be more effective when they are delivered by the intranasal route, particularly if these are the routes of infection.

Therefore, many drugs are delivered by nasal routes. The advantages of nasal routes of delivery are included targeting the drug to the site of infection or disease, rapid absorption into the bloodstream, and easier needle-free delivery.

The nasal delivery route has a number of absorbing advantages over other routes of administration, like-non-invasiveness, rapid attainment of therapeutically relevant concentrations to the bloodstream, no first-pass metabolism, ease of administration and, etc. Mainly the nasal delivery system has the potential to enable drug developers in creating innovative medicines by using already approved products by delivering them through new routes of administration.

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Mechanism of nasal absorption-

The first step in the absorption of drugs from the nasal cavity is the passage through the mucus, where the large or charged particles may find it more difficult to cross. But the small uncharged particles are easily pass through this layer by the mechanisms for absorption through the nasal mucosa. These are including in paracellular transport via movement between cell and transcytosis by vesicle carriers, transcellular or simple diffusion across the membrane.

The first mechanism of nasal absorption is included in an aqueous route of transport, which is also known as the paracellular route. This route is slow and passive, where the inverse log-log relationship between intranasal absorption and the molecular weight of water-soluble compounds. Bioavailability with a poor effect was observed for drugs with a molecular weight greater than 1000 Daltons.

The second mechanism of nasal absorption is transporting a lipoidal route, which is known as the transcellular process. It is responsible for the transport of lipophilic drugs that show a rate of dependency on their lipophilicity. Drugs also cross the membrane by an active transport route through the carrier-mediated means or transport through the opening of junctions.

For example-Chitosan which a natural biopolymer, which opens tight junctions between epithelial cells to facilitate drug transport.

You may read- Drug dosage form.

Factor influencing the nasal drug absorption/ nasal dosage form-

1) Factors Related to Drug-

Molecular weight where the permeation of drugs is less than 300 Dalton which is not significantly influenced by the physicochemical properties of the drug.

Chemical Form is the vital parameter in drug absorption because the conversion of the drug into a salt or ester form may alter its absorption.

Polymorphism is known to affect the dissolution rate and solubility of drugs in their absorption through biological membranes. So, it is more important that polymorphic stability and purity of drugs for nasal powders and suspensions should be studied.

Solubility and Dissolution rate is for better absorption drugs which help to get dissolved. If particles are present, then it may difficult for absorption.

-As Lipophilicity goes on increasing it increases permeation through the nasal mucosa. Lipophilic compounds tend to readily cross biological membranes through the transcellular route. Since they are able to partition into the lipid or bilayer of the cell membrane and diffuse into which transverse the cell in the cell cytoplasm. Testosterone has been absorbed nasally, which is already proved in animal models.

Partition Coefficient and pKa are as pH partition theory which states that unionized species are absorbed well as compared with ionized. Hence it is the same in the case of nasal absorption also.

2) Factors Related to Formulation-

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

-The higher viscosity of the nasal formulation increases the contact time between the drug and the nasal mucosa thus increasing the time for permeation. At the same time, highly and viscous formulations interfere with the normal functions like ciliary beating or mucociliary clearance and thus alter the permeability of drugs.

-Optimum osmolarity should maintain as it causes shrinkage of the nasal epithelial mucosa and alters the permeation of drugs.

Buffer Capacity of a nasal formulation is generally administered in small volumes ranging from 25-20 μL. Hence, the nasal secretions may change the pH of the administrated dose. That can affect the concentration of unionized drug which is available for absorption. Hence, an adequate formulation of buffer capacity may be required to maintain the pH.

Drug Concentration, Dose, and Dose Volume are three interrelated parameters that are impacting the performance of nasal delivery performance. Nasal absorption of L-Tyrosine was the point to increase with drug concentration in nasal perfusion experiments.

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3) Physiological Factors-

Effect of Deposition on Absorption, where the deposition of the formulation in the anterior of the nose provides a longer nasal residence time. The anterior portion of the nose is an area of low permeability, while the posterior portion of the nose where the drug permeability is generally higher provides a shorter residence time.

Nasal Blood Flow, where the nasal mucosal membrane is very rich in vascular and plays a vital role in thermal regulation. Also, in the humidification of the inhaled air where the drug absorption will depend upon the vasoconstriction and vasodilation of the blood vessels.

Effect of Enzymatic Activity, where several enzymatic that are present in the nasal mucosa might affect the stability of drugs. For example, proteins and peptides are subordinated to degradation by proteases and aminopeptidase at the mucosal membrane. The level of aminopeptidase present is too lower than that in the gastrointestinal tract. Peptides may also form complexes with immunoglobulin (IgS) in the nasal cavity which leads to an increase in the molecular weight and a reduction of permeability.

Effect of Mucociliary Clearance, where the absorption of drugs is influenced by the residence or contact time between the drug and the epithelial tissue. The mucociliary clearance is inversely related to the residence time and thus inversely proportional to the absorption of drugs administered.

Effect of Physical Condition, where the nasal pathologies may affect the nasal mucociliary transport process and also the capacity for nasal absorption. In the times when the mucosa is crushing, bleeding, or dry. When someone may be suffering from rhinorrhea, sinusitis, or nasal infection. In people who are suffering from severe nasal allergies, excessive nasal secretion can wash away the formulation before the drug has a chance of getting absorbed through the mucosa or before acting locally.

Appropriate drug candidate for nasal delivery/ nasal dosage form-

-Appropriate aqueous solubility to provide the desired dose in a 25-150μL volume of the formulation administered per nostril.

-Appropriate nasal absorption properties.

-No nasal irritation from the drug should be there.

-An appropriate clinical rationale for nasal dosage forms e.g. Rapid onset of action.

-The low dose generally 25mg per dose.

-No toxic metabolites.

-No offensive odors associated with the drug.

-Suitable stability characteristics.

Nasal drug delivery system dosage forms-

The selection of drugs for nasal dosage form completely depends upon the drug that is used, proposed indication, patient population, and marketing preferences also.

-Liquid Nasal Formulations-

These are the most widely used dosage forms for the nasal administration of drugs. These are mainly based on the aqueous state formulations. Their humidifying effect is convenient and very useful since many allergic and chronic diseases are often connected with crusts and the drying of mucous membranes.

The effect of microbiological stability, irritation, and allergic rhinitis are the major drawbacks associated with the water-based dosage forms because these required preservatives impair mucociliary function.

1. Instillation and rhinyle catheter- Catheters are used for the purpose to deliver the drops at a specified region of the nasal cavity easily. Place the formulation inside the tube and which kept the tube at one end was positioned in the nose, and the solution was administered into the nasal cavity by blowing through the other end by mouth.

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

3. Squeezed bottle- These are mainly used as a delivery device for decongestants. These are included as a smooth plastic bottle with a simple jet outlet. When pressing the plastic bottle, the air inside the container is pressed out from the small nozzle, thus atomizing a certain volume. By releasing the pressure again in the same way, the air is drawn inside the bottle. Through the procedure often results in contamination of the liquid by microorganisms and nasal secretion sucked inside.

Metered-dose-pump-nasal-sprays
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4. Metered-dose pump sprays- Most of the pharmaceutical nasal preparations in the market are containing solutions, emulsions, or suspensions which are delivered by metered-dose pump sprays. Nasal sprays, or nasal mists, are used for the nasal delivery of a drug, that either used locally to generally alleviate cold or allergy symptoms such as nasal congestion or systemically.

Although the process of delivery varies, most nasal sprays function by instilling a fine mist into the nostril by the action of a hand-operated pump mechanism. The main types are available for local effect are antihistamines, corticosteroids, and topical decongestants.

Metered-dose pump sprays are included in the container, the pump with the valve, and the actuator.

B. Powder Dosage Forms

Dry powder forms are less frequently used in nasal drug delivery. These dosage forms are the lack preservatives and the improved stability of the formulation with its major advantage. As compared to solutions, the administration of powders could result in prolonged contact with the nasal mucosa.

1. Insufflators are the devices to deliver the drug substance for inhalation. It can be fabricated by using a straw or tube which contains the drug substance and sometimes it may contain a syringe also.

The achieved particle size of this system is often increased compared to the particle size of the powder particles due to insufficient disaggregation of the particles. It results in a high coefficient of variation for initial deposition areas. Many insufflator systems work with pre-dosed powder doses in the form of capsules.

2. Dry powder inhalers are the devices through which a dry powder formulation of an active drug is delivered for local or systemic effects through the pulmonary route. These are bolus drug delivery devices that contain the solid drug, suspended, or dissolved in a non-polar volatile propellant or in a dry powder inhaler that is fluidized when the patient inhales.

These are mainly used to treat respiratory diseases such as asthma, bronchitis, emphysema, and COPD and also used in the treatment of diabetes mellitus. The medication is mainly held either in a capsule for manual loading or in a proprietary form inside the inhaler.

Once loaded, the operator puts the mouthpiece of the inhaler into their mouth and takes a deep inhalation, by holding their breath for 5-10 seconds. There are many varieties of such devices. The dose which may be delivered is typically less than a few tens of milligrams in a single breath because larger powder doses may lead to provocation of cough.

C. Pressurized metered-dose inhaler-

A metered-dose inhaler (MDI) is a device that delivers an exclusive amount of medication to the lungs, in the form of a short explosion of aerosolized medicine that is inhaled by the patient. It is the most generally used delivery system for the treatment of asthma, chronic obstructive pulmonary disease (COPD), and other respiratory diseases.

Pressurized-metered-dose-inhaler
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The medication in MDI is most generally a bronchodilator, corticosteroid, or a combination of both for the treatment of asthma and COPD. Other medications less commonly are used but also administered by MDI are mast cell stabilizers, such as cromoglicate or nedocromil.

The advantages of MDI are their portability and small in size, availability over a wide dosage range per actuation, dose consistency, dose accuracy, protection of the contents. These are rapidly ready for use. Propellants in MDI are typically making up more than 99 % of the delivered dose. The actuation of the device releases a single metered dose of the formulation which contains the medication either dissolved or suspended in the propellant.

The breakdown of the volatile propellant into droplets then followed by rapid evaporation of these droplets, which results in the generation of an aerosol consisting of micrometer-sized medication particles that are then inhaled.

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D. Nasal Gels-

These are high-viscosity thickened solutions or suspensions. Until the recent development of appropriate dosing devices, there was not much interest in this system. The advantages of a nasal gel are including in the reduction of post-nasal drip due to high viscosity.

Nasal-gel
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Reduction of taste that impacts due to reduced swallowing, reduction of anterior leakage of the formulation, reduction of irritation by using soothing or emollient excipients, and target delivery to mucosa for better absorption is formed.

The declaration of the gel in the nasal cavity depends on the mode of administration because due to its viscosity the formulation has poor spreading abilities. Without any special application techniques, it only occupies a narrow distribution area in the nasal cavity, where it is placed directly.

Excipients used in Nasal dosage form-

-Bioadhesive polymers

-Gelling agent

-Penetration enhancers

-Solvent

-Buffer

-Solubilizer

-Preservative

-Antioxidant

-Humectant

-Surfactant

Advantages of nasal dosage form-

1) Drug degradation is observed in the gastrointestinal tract which is absent.

2) Hepatic first-pass metabolism is avoided with the effect.

3) There is rapid drug absorption and quick onset of action can be achieved.

4) The bioavailability of larger drug molecules may be improved by means of absorption enhancers or other approaches.

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

6) Drugs that are not orally absorbed can be delivered through systemic circulation by nasal drug delivery.

7) The nasal route is an alternative to the parenteral route, especially, for protein and peptide drugs.

8) Suitable for the patients, especially for those who are using long-term therapy, when compared with parenteral medication.

9) Drugs possessing poor stability in G.IT. fluids are given by the nasal route.

10) Polar compounds show poor oral absorption that may be particularly suited for this route of delivery.

11) These are non-invasive therefore reduced the risk of infectious disease transmission.

12) Fast onset of therapeutic action with their effect.

13) There is a reduced risk of overdose.

The disadvantage of nasal dosage form-

1) The histological toxicity of absorption enhancers used in the nasal drug delivery systems is not yet clearly installed.

2) Comparatively inconvenient to patients when compared to oral delivery systems because there is a possibility of nasal irritation.

3) The nasal cavity provides a miner absorption surface area when compared to GIT.

4) There is a risk of tropical side effects and irreversible damage of the cilia on the nasal mucosa, those both from the substance and from constituents added to the dosage form.

5) Certain surfactants are used as chemical enhancers which may disrupt and even dissolve membrane in high concentration.

6) There could be mechanical harm of the dosage form into the other parts of the respiratory tract like- in the lungs because of the inappropriate technique of administration.


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