Department of pharmaceutics, Arvind Gavali College of Pharmacy Jaitapur, Satara 415004, Maharashtra, India.
Nasal drugs delivery has drawn a lot of interest as a practical, trustworthy,and encouraging approach to systemic drug delivery. It is specifically for compounds that are ineffectual when taken orally and only work when delivered intravenously. The nasal route offers benefits over other non-invasive medication delivery techniques.. The current review discusses nasal delivery technologies while acknowledging their advantages and disadvantages. This review's objective is to present information on nasal medication delivery systems, including their benefits, drawbacks, drug absorption methods, nasal cavity anatomy, and variables influencing nasal drug administration.Methods for improving absorption through the nose, and methods for extending the half-life of nasal drug formulations.
Because it's simple of manufacture and oral method of administration is the preferred and applied mode of medicine delivery. Research on alternative drug delivery methods began as a result of inadequate gastrointestinal absorption.[1] The Ayurvedic system of Therapy is accepted in Indian medicine administered intravenously as a kind of treatment. Moredrugshave recently demonstrated that have larger oral nasal administration bioavailability when given orally.[2]The nasal mucosa is perfect for systemic medication transport due to its high penetrability, high vascularity, and less enzymatic circumstances. Nasal delivery of protein and peptide molecules appeals to formulation scientists due to its non-intrusiveness and ease of administration. [3]
Physiology And Nasal Anatomy
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Fig. 1The Nasal Cavity's Anatomy
To evaluate medication absorption through the mucous membranes of the nose, it is crucial to comprehend the architecture and nasal physiology and its connection to the delivery system's operations method used.. The nasal channel that connects themto the nasopharynx via the nasal vestibule is around 12–14 cm deep. The mucus that shields the mucosa from the inspired air is in close contact withthe nasal cellular machinery in this channel. [1] the nasal canals' vestibular, respiratory, and olfactory areas constitute three distinct functional zones.[2] The human nasal cavity has a about total expanse 180cm2 and a volume of roughly 16–19 ml. The septum divides it into two nasal chambers. The following are descriptions of a few of the regions.
3) The system of vestibular[2]
It is in charge of eliminating particles in the air and is located at the beginning of the nasal passages. It is thought to be the least important of the three zones in terms of drug absorption.
The Region of Olfactory
Because of its approximately 10 cm2 surface area, it is crucial for the delivery of drugs to the brain and CSF. The olfactory epithelium is supported by the lamina propria, a thick connective tissue found in the human olfactory area. Blood arteries, axons, and the Bowens bundle are found in the lamina propria, whereas the epithelium is made up of three different cell types: olfactory receptor cells, supporting cells, and basal cells. Neurones are found between the supporting cells. A single dendrite that extends from the cell body to the free apical surface of olfactory receptor cells, also known as bipolar neurones, terminates in an olfactory knob that protrudes above the epithelium and is furnished with nonmotile cilia.2]The mucus layer that protects the epithelium of the nose passages collects dust particles. Every 10 to 15 minutes, the cilia in the nasal cavity remove the mucosal secretions, which have a pH of 5.5 to 6.5 in adults. The nasal cavity contains a variety of enzymes, including glutathione S-transferase, carboxyl esterase, and cytochrome P-450.
Mechanism Of Nasal Absorption [4]
The death A medication's first step of absorption occurs through the nasal cavity's mucus; large or charged particles may find this more difficult. However, tiny, unchanged particles can readily pass through this layer due to the nasal mucosa's absorption mechanisms. These include paracellular transport through cell-to-cell motion, vesicle-mediated transcytosis, transcellular, or straightforward membrane dispersion.[4]
1. The first process includes the water transport system, often known as the paracellular pathway. Intranasal absorption is a slow and passive pathway with an inverse log-log relationship to the molecular weight of water-soluble substances. Decreased bioavailability was seen for medications having a molecular mass greater than 1000 Daltons..[1]
2. The second mechanism transports medications that are lipophilic and have a rate dependence on their lipophilicity via a lipoidal pathway known as the transcellular process. Drugs can also pass through membranes actively, either by junction opening or carrier-mediated methods. To help in drug delivery, a natural biopolymer called chitosan can be used to open tight connections between epithelial cells.[1, 4]
Fig No.2 Mechanism of Nasal Absorption
Advantage Of Nasal Drug Delivery System [5,6,7,8]
1. Directly enter the systemic blood circulation rather than passing through the liver and intestinal digestion first.
2. Drug degradation does not occur in the GIT tract.
3. The onset of action and the rate at which drugs are absorbed.
4. The bioavailability of drugs is better for smaller molecules.
5. It offers low molecular weight medicines, particularly lipophilic ones, good penetration.
6. Through the mucosa of the nose.
7. Lipophilic drugs can quickly cross the BBB.
8. Rapid medication absorption occurs through highly vascularized mucosa.
9. Ample nasal mucosal surface area is available for dosage absorption.
10.The action quickly begins.
11. non-intrusive and simple to administer.
12. Get around the BBB.
13. Drug degradation seen in the GIT is prevented.
14. There is no hepatic first pass metabolism.
15. Small medication molecules are well absorbed through the nasal cavity.
16. Absorption enhancers can boost the bioavailability of big pharmacological molecules.
17. Drugs that are inappropriate for oral administration can be successfully administered by nasal administration.
18. An alternative to parenteral delivery, especially for peptides and proteins.
Disadvantage Of Nasal Drug system of Delivery [9-11]
1. In comparison to the gastrointestinal tract, there is less surface area available for absorption in the nasal cavity.
2. Unlike oral delivery, discomfort is a possibility.
3. The drug and ingredients in the dosage form may cause long-term damage to the cilia of the nasal mucosa in addition to local side effects.
4. A dose form mechanical loss into the lungs or additional areas of the respirational tract could occur as a result of inappropriate delivery methods.
5. Certain surfactants that are used as chemical boosters might harm or even dissolve the membrane when they are present in high enough concentrations.
Agents Impacting Nasal Drug Absorption
A) Drug-Associated Factors[1, 6]
1. Chemical Weight: The physical and chemical properties of the substance have small outcome on the penetration of drugs with molecular weights lower than 300 Dalton.
2. Chemical System: A medication's chemical formula is an essential factor in how well it is absorbed since it can change if it is transformed in the form of salt or ester.[1]
3. Polymorphism: The effects of polymorphism on a drug's solubility, rate of dissolution, and capacity tocross biological membranes are well known. Research on the polymorphous steadiness and medicine purity for nasal precipitates and/or solutions is therefore essential.[7]
4. Solubility and Rate of Dissolution: For better absorption, medications should dissolve. Particles make absorption a little more difficult.
5. Lipophilicity: The nasal mucosa becomes more permeable to the drug as lipophilicity increases.Because lipophilic chemicals can penetrate into the lipid (bilayer) of biological membranes and diffuse into and travel through the cell into the cytoplasm,
Often, it is simple to penetrate Biological membranes go from one cell to another. In physical trials, medications such as testosterone have previously shown nasal absorption.
6. pKa and the partition coefficient:
Since nonionized chemicals are better absorbed than ionized ones, according to the theory of pH partitioning, nasal absorption occurs similarly.[1]
B) Formulation-Related Factors [8]
1. pH: The effectiveness of a medication's penetration can be affected by both the formulation's pH and the nasal surface's pH. To avoid nasal pain, the pH of the nasal formulation must be adjusted to 4.5–6.5.
2. Viscosity: Higher viscosity formulations prolong the duration of the medication's contact with the nasal mucosa, which prolongs the time it takes for penetration. Furthermore, formulations that are too viscous hinder the permeability of medications by disrupting normal functions such mucociliary clearance and ciliary beating.
3. Osmolarity: Maintaining optimal osmolarity is important because it decreases the size of the nasal epithelial mucosa and influences how drugs penetrate the nasal mucosa.
4. Nasal formulations typically have a buffer capacity of: provided in minuscule volumes ranging from 25 to 20 L. As a result, nasal secretions may alter the pH of the dosage. This may have an effect on the amount of union-produced medications that are available for absorption. It can be necessary to have a enough formulation buffer capacity in order to maintain the pH.
5. Drug dosage, dose volume, and drug absorption: These 3 interrelated factors move the effectiveness of nasal distribution. They are Concentration of Drugs, dose, and dose volume. It was shown that L-Tyrosine nasal absorption rose with medication concentration in nasal perfusion testing.[8]
C) Biology-Related factor
1. The impact of deposition following absorption: The nasal residency period is prolonged by placing the formulation in the front of the nose. While the posterior portion of the nose, where drug permeability is often higher, provides shorter habitation periods, the front portion of the nose has low permeability.
2. Nasal Blood Flow: The ability of a medicine to be absorbed will depend on how well the blood vessels dilate and contract since the nasal mucosal membrane has a high concentration of blood vessels and is crucial for regulating the air's temperature and humidity.[4]
3. Effect of Enzymatic Activity: Numerous enzymes found in the nasal mucosa may have an impact on the stability of medications. For instance, proteins and peptides are broken down at the mucosal membrane by proteases and amino peptidases. Compared to the gastrointestinal tract, there is a significant decrease in the amount of amino peptidase present. Peptides and immunoglobulin (IGS) can mix in the nasal cavity to form complexes that have a higher molecular weight and lower permeability.
4. Mucociliary Clearance Effect: The total of time a medicine spends in residence (contact) with the epithelial tissue has an impact on how well it is absorbed. Mucociliary clearance, which is inversely connected with residence time, is inversely correlated with drug absorption.
5. Impact of Physical Health:Nasal mucociliary transport and/or nasal absorption ability may be impacted by intranasal diseases. The mucosa may occasionally be dry, bleed, or compress. There could be sinusitis, rhinorrhea, or a nasal infection. Excessive nasal discharge from severe nasal allergies may wash away the medication's formulation before it may begin to function locally or pass through the mucosa.
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Figno.4: Factors Influencing the Nasal Drug Absorption
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Drug Formulations for The Nose Are Evaluated [16, 17]
Studies on nasal permeation in culture. There are several methods used to calculate the formulation's drug diffusion across the nasal mucosa. To examine the drug diffusion profile, there are two distinct approaches.
(A)In vitro diffusion studies
The nasal diffusion cell was built out of glass. The recipient chamber holds 60 milliliters and is water-jacketed. The lid features three openings: one for a sample, one for a thermometer, and one for a donor tube chamber. The donor chamber has an interior diameter of 1.13 cm and measures 10 cm in length. A donor tube chamber has a flanged top that is about 3 mm thick and a total capacity of 60 ml. After being removed from the sublayer bone tissues, the sheep's nasal mucosa was stoned in distilled water containing a few drops of gentamycin. Before the donor chamber tube is connected, all blood from the muscosal surface is extracted.The donor chamber tube is positioned so that it only touches the diffusion medium of the recipient chamber. 0.5 ml samples are taken from the recipient chamber and put into amber-colored ampoules at regular intervals. The extracted sample are suitably substituted. An appropriate analytical approach is used to estimate the drug content of the samples. 37 °C is the constant temperature at which the experiment is carried out.
(B) Studies on In Vivo Nasal Absorption
Animal models for research on nasal absorption There are two kinds of animal models used in nasal absorption research: entire animals, or in vivo models, and isolated organ perfusion, or ex vivo models. Below is a detailed discussion of these models: Rat model The operation For in vivo studies on nasal absorption, rats are prepared as follows: The rat is anesthetized by intraperitoneal injection of sodium pentobarbital. A polyethylene tube is used to cannulate the trachea following a neck incision. A second tube is inserted into the rear of the nasal cavity through the oesophagus. The nasopalatine tract is closed to stop the medicinal solution from draining from the nasal cavity through the mouth. The drug solution is administered to the nasal cavity by either the nostril or the cannulation tube. The femoral vein is where the blood samples are extracted. Due to the obstruction of all possible drainage channels, the medication can only be absorbed and administered into the systemic circulation.
Rat model
The following is how rats are surgically prepared for an in vivo nasal absorption study: Sodium pentobarbital is injected intraperitoneally to put the rat to sleep. A polyethylene tube is used to cannulate the trachea after a neck incision is done. An additional tube is sent through the oesophagus and into the nasal cavity's back.To prevent the medication solution from being emptied via the mouth from the nasal cavity, the nasopalatine tract channel is blocked. Either the nostril or the cannulation tubing is used to transfer the medication solution to the nasal cavity. Blood samples are taken from the femoral vein. Because all possible drainage outlets are blocked, the drug can only be absorbed and transported into the systemic circulation by penetration and/or diffusion through the nasal mucosa. A rabbit model The following are some advantages of using rabbits as an animal model for nasal absorption research:
1. Pharmacokinetic investigations with large animals (like monkeys) are made possible by it.
2. It is easily maintained in scientific environments, readily available, and reasonably priced.
3. The blood volume (about 300 ml) is sufficient.
4. to enable regular blood draws (l–2ml). It so makes it possible to fully characterize the absorption and determine the drug's pharmacokinetic profile. Depending on the goal of the study, rabbits (about 3 kg) are either kept conscious or put under anesthesia. In the anesthetized model, a ketamine and xylazine combination is injected intramuscularly into the anesthetized rabbit. The rabbit's head is held upright while a nasal spray of the drug solution is sprayed into each nostril. Throughout the experiment, the rabbit's body temperature is maintained at 37°C using a heating pad. Blood samples are taken from the marginal ear vein or artery using an indwelling catheter.
Rabbit model
When used as an animal model for research on nasal absorption, rabbits have a number of benefits.
1. It allows for pharmacokinetic research using large animals (such as monkeys).
2. It is reasonably affordable, widely accessible, and simple to maintain in scientific settings.
3. There is sufficient blood present (about 300 ml).
4. To enable routine blood sample (1–2 ml).
This makes it possible to fully characterize absorption and determine the drug's pharmacokinetic characteristics. Depending on the investigation's objectives, 3 kg of rabbits are either anesthetized or kept awake. In the anesthetized model, xylazine and ketamine are injected intramuscularly into a rabbit that is under anesthesia. The rabbit's head is held up as a medicine solution is sprayed into its nasal passages. A heating pad is used to keep the rabbit's body temperature at 37°C throughout the experiment. An indwelling catheter is inserted into a marginal ear vein or artery to collect blood samples.
Models of Ex Vivo Nasal Perfusion
Investigations of In-Vivo Bioavailability
Table 1-Formulation and Active Agents Used for Nasal Drug Delivery
|
Sr.no. |
Formulation |
Active Agent |
|
1. |
In-situ Nasal Gel |
Midazolam, Insulin, Triptans, Diltiazem |
|
2. |
Nasal Inserts |
Chlorpromazine, Albuterol |
|
3. |
Microspheres |
Beta-Amyloid Fibril, Starch Microspheres, Dextran Gentamicin, Insulin, Desmopressin |
|
4. |
Microparticles |
Serum albumin, Thiolate Chitosan Microparticles |
|
5. |
Dry Powder |
Zolmitriptan |
|
6. |
Nasal Gel |
Oxytocin, Metoclopramide Hydrochloride |
Marketed Preparation [26, 27]
Nasal drug products (proteins and peptides) for systemic drug delivery in the market:
Table2.Nasal drug products for systemic drug delivery in the market
|
Drug Substance (Product name) |
Indication |
Dosage form |
Status |
Manufacturer |
|
Salmon calcitonin (Karil 200 I.E.) |
Osteoporosis |
Solution (spray) |
Marketed |
Novartis Pharma |
|
Desmopressin (Minirin Nasenspray) |
Antidiuretic hormone |
Solution (spray |
Marketed |
Ferring Arzneimitted |
|
Buserelin (Profact nasal) |
Buserelin |
Solution (spray) |
Marketed |
Aventis Pharma |
|
Nafarelin (Synarela) |
Endometriosis |
Solution (spray) |
Marketed |
Pharmacia |
|
Oxytocin (Syntocinon) |
Lactation induction |
Solution (spray) |
Marketed |
Novartis Pharma |
Table 3: Nasal Drug Products (NonPeptide) For Systemic Drug Delivery in the Market
|
Drug Substance (Product name) |
Indication |
Dosage form |
Status |
Manufacturer |
|
Zolmitriptan (Asco Top* Nasal) |
Migraine |
Solution(spray) |
Marketed |
Astra Zeneca |
|
Sumatriptan Imigran* Nasal |
Migraine |
Solution(spray) |
Marketed |
Glaxo SmithKline |
|
Dihyfroergotamin (Migranal* Nasal Spray) |
Migraine |
Solution(spray) |
Marketed |
Novartis Pharma |
|
Estradiol (Aerodiol*) |
Hormone replacement |
Solution(spray) |
Marketed |
Servier |
The Nasal Dosage Forms Have Advanced
1. Nasal Drops: The nasal drop is among the most straightforward and useful nasal delivery devices ever developed. Nasal drops may not be suitable for prescription drugs due to the lack of dose precision in this approach. Reports indicate that nasal drops are more effective than nasal spray at delivering human serum to the nostrils.18]
2. Nasal Spray: Solutions or suspensions can be used to create nasal spray formulations. A nasal spray can administer a precise dosage because metered dose pumps and actuators are readily available. These are improved than powder sprays since the latter irritates the mucosa.
3. Nasal Powders: This dosage form may be made if solution and suspension dosage forms cannot be made, for instance, due to the drug's volatility. The benefits of the nasal powder dosage form include no preservative and improved formulation stability. However, the suitability of the powder formulation depends on the solubility, particle size, aerodynamic properties, and nasal irritancy of the active drug and/or excipients. This method also has the advantage of enabling local drug application.[18]
4. Nasal Gel: Due to its high viscosity, decreased post-nasal drip, decreased taste impact from swallowing less, decreased anterior formulation leakage, reduced irritation from the use of calming and emollient excipients, and targeted delivery to the mucosa for improved absorption, the nasal gel attracted increasing interest. The nasal gel showed growing interest due to reduction of post-nasal drip, 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 delivery to mucosa for better absorption.[19]
5. Nasal Inserts: Nasal inserts are novel solid, bio adhesive dosage forms that provide prolonged systemic medication delivery via the nasal route. The fundamental idea behind the dosage form is to avoid the sensation of a foreign body by removing nasal fluid from the mucosa after delivery and forming a gel in the nasal cavity.[18]
Brand New Intranasal Medication Delivery System For CNS.[20]
a) Microemulsion
The microemulsion system has the potential to deliver in thenasally. Microemulsions are often combined with a co-surfactant. The systems are currently of interest to pharmaceutical scientists because of their potential to integrate a range of pharmacological chemicals and act as drug delivery vehicles. Drug solubilization and bioavailability, thermodynamic stability, ease of manufacturing and scaling up, and spontaneously production are some of the advantages. A complete understanding of the microemulsion's structure, phase behavior, thermodynamic stability factors, factors affecting drug release from the formulation, ideal microemulsion excipient requirements, and the potential applications and limitations of the microemulsion system is required to prepare a pharmaceutically.
b) Nano-particles
c) Microsphere
d) Nasal In-situ Gels
In-situ gel formulations are drug delivery systems that are in solution form prior to administration to the body but undergo gelation to form gel after administration. This can be accomplished using a variety of polymers, such as carbopol, polxamers, PVA, and chitosan.
Applications
Vaccine Delivery via Nasal Route: The nasal mucosa is the first site of contact with inhaled pathogens; both mucosal and systemic immune responses are generated; nasal passages are abundant in lymphoid tissue; and nasal vaccine delivery is safe, non-injectable, affordable, and patient-friendly. In addition to a systemic immune response, nasal vaccination has been shown to produce a local immunological reaction in the nasal lining, providing an extra layer of defense. (Mestecky J et al., 1997). The vaccine induces the formation of local secretory IgG and IgA antibodies by injecting it directly into the nasal cavity, adding an additional line of defense that helps eradicate the illness before it has a chance to take hold.
Nasal decongestant:
With low therapeutic dosages and few systemic negative effects, the nose is used to address localized issues. Low molecular weight medications that are hydrophobic or water soluble are utilized to address regional pathogenic conditionsin the nose. Colds are also treated by using nasal decongestants, including xylometazoline.
Systemic Effects: Nasal administration is appropriate for acids-labile medications, peptides, and proteins62 when a prompt reaction is needed, such as in the treatment of migraines.Peptide and protein medications have a lower bioavailability (1–2%) due to their increased molecular weight and polarity, which makes it difficult for them to pass through the nasal mucosal membrane. However, the absorption of progesterone and propranolol through the nasal epithelium is similar to that of parenteral delivery63.By adding permeation enhancers to the formulation and using bioadhesive agents to prolong the drug's contact time with the mucosal membranes, less bioavailability can be improved. When 0.1 percent N-succinyl chitosan was used as a permeation enhancer in rats, the relative bioavailability of isosorbide dinitrate increased significantly (to 69.85 percent) compared to the control groups (43.32 percent) and the 0.5 percent ...
Marketed Nasal Formulation
1. Nasal Drop
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Fig. 1 Ephedrine Nasal Drops 0.5% w/v
2. Nasal Spray
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Fig. 2 Vicks Vapospray
3. Nasal Gel
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Fig. 3 Nasal Antisnoring Inserts [16
CONCLUSION: -
There is new hope for the local and systemic distribution of medications due to the passage of drug molecules over the nasal mucosa. Another method of delivering drugs that work on the central, systemic, and local nervous systems is nasal drug delivery. Its benefits include reducing systemic exposure, which lessens adverse effects, and preventing first-pass metabolism.
However, to create a workable nasal drug, several obstacles to the intranasal route need to be removed. Nasal absorption is largely affected by physiological circumstances, the physicochemical characteristics of the drug, and formulation. Future research will be crucial to increasing the effectiveness and attractiveness of this distribution strategy.
REFERENCES
Smita Borkar, Monika Bhosale*, Arati Lohar, Dr. V. Y. Lokhande, Review on Nasal Drug Delivery System, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 4, 3424-3438 https://doi.org/10.5281/zenodo.15309915
10.5281/zenodo.15309915
