Oral administration of medicines is the most convenient method of drug dispensing with the highest compliance rates, as patients can self-administer their medications in a noninvasive and painless manner, providing a variable and customizable dosing schedule at home [1]. On the other hand, the harsh chemical environment in the stomach and intestines, the first-pass effect, and the barrier of the gastrointestinal tract pose major difficulties for the efficacy of drugs ^[2][3][2,3]. Thus, alternative routes of administration have been developed to circumvent those hurdles and achieve the requisite results (Figure 1). The major alternative routes are pulmonary, transdermal, buccal, nasal, and parenteral [2], and each of these has its own advantages and disadvantages, as shown in Table 1.

Intranasal absorption is a favored route because it avoids the gastrointestinal and hepatic metabolism, leading to an increase in drug bioavailability, and a reduction in the side effects and the required dose administered [4]. Furthermore, the intranasal route also has several practical advantages for both the patient and the pharmaceutical industry. The former can benefit from the non-invasive, highly tolerable, easy to administer, and pain-free drug delivery systems, and pharma avoids the need to sterilize the nasal products [5]. Moreover, acid-sensitive drugs, such as biologics (peptides, hormones, etc.), which are prone to degradation in the gastrointestinal tract, and drugs that cannot be absorbed orally, may be administered nasally. The inclusion of enhancers, mainly excipients, can increase the nasal absorption of such drugs [6]. Recently, many pharmaceutical companies have become involved in the commercialization of absorption promoters and absorption modulators for nasal drug delivery [7].

Even though the nasal epithelium acts as a tight barrier, the intercellular junctional complex of the nasal mucosa is not impervious, due to the leaky epithelial tissue ^[8][9][8,9]. Thus, in combination with the high vascularization of the nasal surface, a favorable profile for therapeutic purposes, more than just the topical nasal drug delivery is achieved ^[10][11][10,11].

2. Anatomy and Physiology of the Nose

The primary roles of the nasal cavity are olfaction and breathing [12]. Nonetheless, the breathing air is filtered, humidified, and headed by the nasal cavity before reaching the lungs, whilst the inhaled particles and pathogens are trapped from the hair and the mucus layer present in the nasal cavity. Other functions of the nasal structure are the metabolism of endogenous substances and the immunological activities ^[13][14][13,14]. The nasal cavity is located between the roof of the mouth and the base of the skull supported from above by the ethmoid bones and from the side by the ethmoid, maxillary, and inferior conchae bones. The entire surface area is almost 150 cm² and has a total volume of 15–20 mL ^[11][15][11,15]. The nasal cavity consist of three definite parts: the vestibule, the respiratory, and the olfactory regions (Figure 2) [16]. The anterior part of the nasal cavity is the nasal vestibule, which is part of the nostrils, covering an area of about 0.6 cm², and includes the nasal hairs (vibrissae) [17]. Histologically this part is covered by a keratinized and stratified squamous epithelium with sebaceous glands [10]. These nasal regions prevent the insertion of toxic materials, but at the same time, drug absorption is also limited [18]. The respiratory region represents the largest part of the nasal cavity. It is split into three turbinates—the superior, middle, and inferior—which are responsible for the humidification and temperature adjustment of the inhaled air [19]. The most important area for systemic drug delivery is the nasal respiratory mucosa, which consists of the epithelium, the basement membrane, and the lamina propria. The epithelium contains the pseudostratified columnar epithelial cells, goblet cells, basal cells, and mucous and serous gland cells. Many of the epithelial cells are coated by microvilli, which enhance the respiratory surface area, and the cilia, which are fine projections essential for mucus transport towards the nasopharynx [20]. The secretory glands and the goblet cells produce mucus through granules filled with mucin, a glycoprotein that define the mucus viscosity. The mucus is deposited as a thin layer (about 5 μm) in the epithelium, composed of water (95%), 2.5–3% of mucin, and 2% of other substances, such as electrolytes, proteins, enzymes, lipids, antibodies, sloughed epithelial cells, and bacterial products [21]. It is responsible for the humidification and warming of the inhaled air, it has a pH between 5–6.5, and it provides protection to the nasal epithelium against foreign particles and drugs ^[22][23][22,23]. The olfactory region is located on the top of the nasal cavity and continues down the septum and the lateral wall. The olfactory epithelium is pseudostratified and consists of specialized olfactory receptor cells essential for smell recognition [24].

3. Nasal Drug Delivery

The nasal route of administration is used for treating local inflammation, allergic and common rhinitis, and nasal congestion. The active compounds that are commonly used against these diseases are antihistamines, glucocorticoids, or decongestants in the form of nasal spray, drops, solutions, gels, or powders and other types of formulations, including emulsions, suspensions, and microparticles ^[6][25][6,25]. The nasal route is used for either local or systemic action. The drug is administered locally for rapid alleviation of the symptoms of the disease, reducing the administered dose, as the drug is placed directly in the affected area, thus avoiding the systemic metabolism. On the other hand, the nasal administration of pharmacologically active substances for systemic action is used in the case of drugs with poor intestinal absorption and limited stability in the gastrointestinal fluids, with extensive hepatic first-pass metabolism, such as biologics and polar drugs ^[10][11][10,11]. The administration of the drug through the nasal passages can also bypass the blood–brain barrier (BBB), so it can be used for central nervous system (CNS) action. This route has been further studied for administrating vaccines ^[11][26][11,26]. The drug absorption through the nose is based on the physicochemical properties of the administered drug. The drug cannot penetrate the mucosa and manifest its action if it has a large size (greater than 1 kDa), a high degree of ionization, or is too lipophilic. Another factor that can affect absorption is the drug’s pH, which may affect the stability and the ionization of the drug, as well as cause nasal irritation. Formulations that have high viscosity can more easily enter the nasal mucosa, but simultaneous, they may be less absorbed. When the hyper- or hypotonicity is very high, the ciliary movement can be altered, resulting in lower absorption [6]. Finally, the drug’s concentration and quantity, the position of the head during administration, the nasal surface, and the physical condition of the dosage form all play a vital role in the absorption of the drug [27].

4. Factors That Affect the Nasal Drug Absorption

Drug delivery through the nasal route of administration has some limitations, which are crucial because they influence drug concentration and bioavailability and therefore, the absorption and the pharmacological effect of the administered drug. The first main barrier is the range of pathological and physiological conditions linked to the nasal mucosa, which can affect the absorption and efficacy of the drug [28]. For example, a physiological change in nasal mucosa based on illness and allergy (irritation and the inflammation of the nasal cavity, which is intensified by itching and sneezing) may influence drug absorption [6]. In addition, there is a restriction regarding the absorption of the poorly water-soluble drugs due to the low volume of the nasal cavity, which reduces the administered amount to 100–150 μL [28]. The permeability also decreases for the polar and large molecules and for peptides and proteins [25]. However, by using the correct excipients, including bioadhesive polymers, enhancers, and enzymatic inhibitors, the drug permeability and residency in the nasal cavity can be improved [29]. Another crucial barrier is the mucociliary clearance (MCC) of the mucosa, which by replacing the mucus layer every ~15 min with 5–6 mm/min, the transmucosal absorption is decreased. The mucus can also decrease the drug absorption by binding the drug to mucin, which is the primary protein of the mucus. While the small moieties can pass through easily, the charged or larger units can be caught in the mucus gel [25]. Mucus also contains different enzymes which can influence the stability of protein- and peptide-based drugs; proteases degrade peptides and proteins by attacking them. These xenobiotic enzymes [e.g., P450 monooxygenase, Phase I enzymes (flavin monooxygenases, aldehyde dehydrogenases, epoxide hydrolases, carboxylesterases, etc.) and Phase II enzymes (glucuronyl and sulphate transferases, glutathione transferase) can also metabolize intranasally administered small-molecule drugs, such as opioids, histamines, corticosteroids, etc. [30]. Last but not least, there will always be concerns about the safety of nasal medicines, even though recent breakthroughs in both in vitro and in vivo models are a major benefit in speeding up clinical development and eventually, the time-to-market of new treatments ^[31][33].

5. Excipients Used in Modified Drug Release Semi-Solid Pharmaceutical Dosage Forms for Nasal Administration

To improve nose-to-brain drug transfer and to extend drug residence time in the nasal cavity, several approaches could be employed, such as the use of semi-solid dosage forms, permeation enhancers, mucoadhesive and temperature responsive gels, or nano-sized drug carriers (Figure 3). In this section, the excipients and methods used in the recent achievements (2017–2022) in the modified release semi-solid formulations for nasal administration are reviewed and summarized, as shown in Table 2.