A Review on Nasal Self-Emulsifying Drug Delivery Systems: An Alternative Approach to Improve Brain Bioavailability of Poorly Water-Soluble Drugs

 

Ghorpade Arti C.*, S. S. Siddheshwar

Pravara Rural College of Pharmacy, Pravaranagar, A/P Loni – 413736, Tal – Rahata, Dist. – Ahmednagar.

*Corresponding Author E-mail: artighorpade2018@gmail.com

 

ABSTRACT:

Neurotherapeutic drugs fail to reach the site of action due to poor bioavailability, poor water solubility, limited permeability, hepatic first-pass metabolism, and the blood-brain barrier. The nasal cavity allows drugs to be delivered directly to the brain, bypassing the blood-brain barrier. The nasal cavity also avoids hepatic first-pass metabolism, enhancing the systemic bioavailability of highly metabolized substances. As a result, most neurotherapeutics have physicochemical properties that necessitate their formulation in lipidic nanosystems as self-emulsifying drug delivery systems (SEDDS). These are isotropic mixes of oils, surfactants, and co-surfactants that, when diluted in water, produce micro or nanoemulsions containing high quantities of lipophilic medicines. SEDDS should prevent drug precipitation at absorption sites, boost permeability through absorptive membranes, and improve labile drug stability against enzymatic activity. When the benefits of SEDDS and the intranasal route for brain delivery are combined, an increase in medication brain targeting and bioavailability might be expected. 

 

KEYWORDS: Brain delivery low, Intranasal, Neurotherapeutics, Self-emulsifying drug delivery system.

 

 


1.    INTRODUCTION:

The prevalence of neurological illnesses has risen in recent years. According to a World Health Organization (WHO) estimate published in 2020, neurological problems affect up to one billion people worldwide. According to global data, 50 million individuals have epilepsy, 62 million have cerebrovascular illnesses, 326 million have migraine, and 24 million have Alzheimer's disease or other dementias. As a result, neurological illnesses are regarded as one of the leading causes of disability and mortality worldwide. Taking this into consideration, efforts are made on a daily basis to find and develop new and effective neuro medicines, even if the majority of new entities fail to enter clinical trials.1

 

Since ancient times, nasal medication administration for systemic effects has been used. In modern

 

pharmaceutics, the nose was predominantly regarded as a conduit for local medication delivery. The inability to distribute protein, peptide-like macromolecules via methods other than parenteral injection prompted scientists to investigate alternate options, including pulmonary and nasal administration.2 The nasal cavity has the advantages of a wide surface area, quick absorption and action, and avoidance of first-pass metabolism. Furthermore, delivery through the nasal cavity is a safe and convenient method. To reach the system circulation, the medicine must be dissolved and permeate via the mucosal tissues.  The nasal cavity, on the other hand, has significant constraints for intranasal delivery, including a short residence period, mucociliary clearance, and a limited administration volume3.

 

Indeed, medication transport to the brain represents a significant challenge, drugs must passes intact via absorptive membranes, avoid the hepatic first-pass effect, and eventually cross the complicated blood-brain barrier (BBB). To cross absorptive membranes and the BBB, molecules must be lipophilic, have a low molecular weight (400Da), be nonionizable at physiological pH, and not be substrates of active efflux transporters.4 To meet these criteria, 40-70% of new chemical entities explored to treat neurological illnesses end up in biopharmaceutical categorization system (BCS) classes II and IV5,6. While class II medications have low water solubility but high permeability at therapeutic levels, class IV pharmaceuticals have low solubility and permeability. This can reduce solubility, absorption rate, and extension, limiting bioavailability and medication beginning of action6.

 

Alternative formulations have been developed to address those problems, with lipophilic Nano systems gaining popularity in recent years. The major purpose of these systems is to keep lipophilic substances in solution after they come into contact with aqueous environments such those found in the gastrointestinal tract (GIT) or nasal mucosa. SEDDS are a form of lipidic nanosystem well-known for their ability to integrate lipophilic BCS class II and IV medicines7. Until now, the oral route has been the primary focus of SEDDS research. Other methods for SEDDS delivery, on the other hand, may be of significant interest, particularly if they allow for better brain targeting of central nervous system (CNS)-active medicines. In this regard, intranasal (IN) delivery of medicines contained in lipidic nanosystems such as SEDDS could be a clinically advantageous option to investigate. The fundamental reason is that the nasal cavity is the only anatomical region that connects the CNS to the external environment. As a result, this route of administration becomes particularly appealing in the treatment of neurological illnesses, because medications can be partially carried directly to the brain, bypassing the BBB. Drugs delivered via the nasal cavity can also enter the brain via blood circulation. This enables for systemic medication absorption without the need to undergo gastrointestinal transit or a hepatic first-pass impact8.

 

2.     Advantages of nasal route:

Systemic nasal absorption of drug is a new attractive alternative to parenteral drug delivery system, as it offers the following advantages

1.     Pulsatile delivery of some medications, such as human growth hormone and insulin, is more likely with NDD.9

2.     Because of the presence of microvilli, there is a significant surface area available for drug deposition and absorption.

3.     The nasal epithelium is very thin, porous, and vascularized. This allows great absorption and quick delivery of ingested drugs into the systemic circulation, allowing therapeutic activity to begin.

4.     Absorbed compounds are delivered directly into the systemic circulation, bypassing the typical first pass metabolic impact seen after oral drug administration.

5.     Drugs can be absorbed directly into the CNS following nasal delivery in certain cases, bypassing the blood-brain barrier.

6.     The nose is flexible to self-medication, which not only reduces therapeutic costs but also increases patient compliance. Overdosage is unlikely, and nasal rinse can be performed to eliminate unabsorbed excess medication.

7.     Because the nasal epithelium's enzymatic activity is lower than that of the GIT or liver, increased bioavailability of medicines, particularly proteins and peptides, can be attained.10

 

3.     Intranasal Administration as an Alternative to the Oral Route in Brain Drug Delivery:

The most common route of drug administration is orally. It is the favored route due to advantages such as non-invasiveness, patient compliance, and ease of drug delivery11. The severe acidic pH (1.5-4) of the stomach, the first-pass metabolic process, and the presence of enzymes (e.g., pepsin and cathepsin) all hinder the delivery of small and macromolecules by this oral route. Furthermore, once the medicine has passed through the biological gastrointestinal barrier, the drug molecule must pass through an even more rigid BBB barrier to reach the CNS. To overcome the issues associated with oral delivery, the parenteral route is suggested as an alternative that has the advantages of immediate beginning of action and can absorb poorly absorbed medicines extremely well. On the other hand, the disadvantages of parenteral delivery include the high cost, the necessity to be sterile, the possibility of infections and nerve injury, and the need for skilled personnel for medication administration12.

 

In recent years, the nasal route for systemic medication delivery has gained more attention. The nasal cavity is appealing as an application location due to unique qualities such as its vast surface area of approximately 150 cm2, considerable vascularization, excellent permeability, and avoidance of hepatic first-pass metabolism13. Small lipophilic medicines are well absorbed by the nasal cavity, with pharmacokinetic profiles similar to those found after intravenous injection, resulting in nearly 100% bioavailability14.

 

Neurotherapeutics are predominantly lipophilic, with low water solubility and, as a result, irregular dissolution following oral administration. Nonetheless, a portion of the injected dose may enter the systemic circulation. However, due to other physicochemical properties such as high molecular weight, these molecules may be hindered in passing through the BBB, making appropriate therapeutic concentrations in the brain difficult to achieve. SEDDS is one of several lipidic nanosystems that have been created to circumvent the drawbacks of oral administration of neurotherapeutics.15


 

Figure 1. Basic factors affecting the permeability of the blood–brain barrier

 


4.     Biological and pharmaceutical considerations for nasal  drug delivery:

4.1.    Nasal anatomy and physiology relevant to nasal drug administration

The nasal cavity is split longitudinally by the nasal septum and extends from the nostrils (nares) to the nasopharynx .The human nasal cavity is only around 12-14cm long, but it has a significant absorptive surface area of 160cm2 due to three bony structures called turbinate’s or conchae (inferior, middle, and superior) that also help in filtering, humidifying, and warming inspired air.16

 

As indicated in Figure 2 the nasal cavity can be anatomically divided into five distinct regions: nasal vestibule, atrium, respiratory area, olfactory region, and nasopharynx. The structural characteristics of the nasal cavity regions that are responsible for its permeability. The septal wall separates the two nasal cavities, which are dominated by three turbinate: inferior (C1), middle (C2), and superior (C4) turbinate’s’, which are primarily responsible for heating and humidification of the cavity. The respiratory region is richly supplied with blood, has a large surface area, and receives the maximum amount of nasal secretions, rendering it most suitable for the permeation of compounds. Permeability is influenced by these parameters, as well as the type of cells, density, and number of cells present in that region. As nasal epithelium is made up of various cell types. The presence of microvilli on cells significantly enhances the area available for drug penetration.17

 

 

Figure 2. Schematic of a sagittal section of the nasal cavity showing the nasal vestibule (A), atrium (B), respiratory area: inferior turbinate (C1), middle turbinate (C2) and the superior turbinate (C3), the olfactory region (D) and nasopharynx (E).

5.     Mechanism of Drug Absorption By Nasal Route:

Drug distribution mechanisms from the nasal mucosa to the brain have been thoroughly explored over the years. Simply put, the nasal cavity is separated into respiratory and olfactory areas. Drugs can reach the systemic circulation or be delivered directly to brain regions via the trigeminal nerve route in the respiratory region. Drugs can be delivered or diffused directly to the brain in the olfactory area via the olfactory mucosa pathway, which is considered the most important direct pathway. Of However, only a portion of the medicine will likely reach the brain, as some may be lost locally owing to mucociliary clearance or enzymatic breakdown. Furthermore, some of the substance will be absorbed into the systemic circulation, disseminated to non-target tissues, and finally removed. Nonetheless, a portion of lipophilic medicines that reach the systemic circulation will still reach the brain via the BBB (indirect pat hway) (Fig. 3).18

 

 

Figure 3: Schematic representation of intranasal (IN) delivery’s direct and indirect pathways.

 

After SEDDS treatment, the mucous layer overlaying the olfactory and respiratory regions is crucial for the production of micro or nano emulsions. When SEDDS is injected into the nasal cavity, the aqueous mucous and cilia flow movement create optimum conditions for self-emulsification (Figure 4). When the produced emulsion droplets come into contact with epithelial cells, they can either release the encapsulated medications or be transported through the same mechanisms that drugs are transported by when they are in the nasal cavity. This is mostly determined by the physicochemical features of SEDDS and the emulsions generated. The viscosity of the formulation determines how long it can be in touch with the mucosa before clearance. The size and PDI of the generated droplets following emulsification are even more critical. The olfactory nerve pathway, as shown in Figure 4, permits medicines to be absorbed via three separate methods.

1.     The first involves drug absorption intracellularly through the olfactory neurons via endocytosis or pinocytosis.

2.     The second pathway is the extracellular transport, in which hydrophilic drugs cross nasal epithelia by paracellular spaces. This transport comprises the tight junctions between endothelial cells or the spaces between the olfactory nerves and the sustentacular cells.

3.     The third option is transcellular/intracellular transfer via epithelial cells. Small lipophilic molecules pass through epithelial cells by passive diffusion or, in the case of larger moieties, endocytosis/transcytosis.

4.     Molecules also enter the brain via indirect systemic pathways from the lamina propria, medicines can be absorbed by the lymphatic or blood systems, reaching systemic circulation, crossing the blood-brain barrier, and eventually reaching the brain.19


 

Figure :4 Intranasal delivery of drugs loaded in self-emulsifying drug delivery systems (SEDDS).

 


6.     Ideal drug candidate for nasal delivery:

1.     Appropriate solubility to provide the desired dose in a 25–150ml volume of formulation administered per nostril; providing the therapeutic effects.

2.     Appropriate nasal absorption properties.

3.     No nasal irritation from the drug.

4.     A suitable clinical rationale for nasal dosage forms, e.g. rapid onset of action.

5.     Low dose, in general, below 25mg per dose.

6.     No offensive odors/aroma associated with drug.

7.     Suitable stability characteristics. 

8.     Molecular weight < 500Da, log P < 5.

9.     Aqueous solubility < 50mg/ml .

10. Drug in solution: pH approximately 5.5, osmolality < 500mosm/kg20.

 

7.     Self-Emulsifying Drug Delivery System:

SEDDSs, SMEDDSs, and SNEDDSs are physically stable isotropic mixes of oil, surfactant, cosurfactant, and solubilized drug material that form fine oil quickly and spontaneously in water emulsions, microemulsions, and nanoemulsions, respectively. The potential benefits of self-emulsifying systems include 100% drug entrapment capacity, physically stable formulation (can also be filled in capsules), no dissolution step required, formation of submicron droplet size, which increases absorption surface area, rate and extent of absorption, and thus bioavailability. SEDDS successfully deliver BCS Class II medicines. They also have the capacity to deliver BCS class III, BCS class IV, and hydrolytically susceptible medicines effectively21. SEDDSs have been defined as systems that generate emulsions with droplet sizes ranging from 100 to 300 nm, whereas SMEDDSs generate transparent microemulsions with droplet sizes of less than 50 nm. However, unless otherwise specified, SEDDS applies to all sorts of self-emulsifying systems, whereas SNEDDS describe systems that generate nano emulsions following dispersion in aqueous environments22.

 

COMPONENTS OF SEDDS:

1.     Oil

2.     Surfactant

3.     Cosurfactant

4.     Drug

 

Figure : 5 Component of SEDDS

 

1.     Oil Phase:

SNEDDSs are typically made from medium- and long-chain triglyceride (TG)-containing oils with variable degrees of saturation. Because of its importance in both formulation-loading capacity and drug absorption, the oil with the greatest potential to solubilize a specific medication is usually chosen. Natural edible oils (such as castor oil, soybean oil, coconut oil, and so on) continue to be the most logical and sought oil constituents, but they have a low drug-loading capacity and poor emulsification efficiency23.

2.     Surfactant:

In SMEDDS, oil phase containing the drug is emulsified into nano sized droplets. As the size of oil phase containing drug decreases to nano size, the effective surface volume increases by several folds and therefore, it requires large concentration of surfactant for its stabilization. However, too large a concentration of surfactant was found to increase the droplet size of the emulsion . During the formulation of SMEDDS, non-ionic surfactants are preferred over ionic surfactants as they are less toxic24.

 

3.     Co-surfactants:

The manufacture of an optimal SMEDDS necessitates rather high surfactant concentrations (usually greater than 30% w/w), yet this causes discomfort. As a result, co-surfactant is employed to lower surfactant concentration. The cosurfactant's role, in conjunction with the surfactant, is to reduce interfacial tension to a very small, even transiently negative value.25

 

4.     Drug:

Various physicochemical parameters of the drug, including as log P, pKa, molecular structure and weight, presence of ionizable groups, and amount, all have a significant impact on SNEDDS performance. The nano emulsion’s droplet size grows as the medication concentration increases.26

Other ingredients such as antioxidants (e.g., ascorbic acid), viscosity enhancers (e.g., chitosan), taste/Odor masking agents (e.g., sorbitol, orange oil), and modified drug release ingredients (e.g., cellulose-based polymers) can be incorporated in SEDDS that have a very low percentage of water in their constitution.

 

8.     Preparation and Physicochemical Characterization of SEDDS:

In terms of preparation (Figure 6), SEDDS are easily made by simply combining all of the components together. The medicine is then added and solubilized to produce a clear liquid solution. At this point, L-SEDDS can either remain liquid or be converted into S-SEDDS. All transformation procedures involve the addition of a solid carrier -    

 

Figure : 6 Preparation of Self-Emulsifying Drug Delivery Systems

 

1. Adsorption

2. spray drying

3.  hot-melt extrusion 

4. freeze-drying.27

 

Methods used for fabrication of nano emulsions:

The methods for producing nano-emulsions (Figure 6) are classified as high-energy emulsification x.


Figure :6 Nanoemulsion Fabrication Methods

 


1.     High-Energy Emulsification Methods:

High-energy emulsification methods employ devices that generate extremely high mechanical energy in order to produce nano emulsions with extremely high kinetic energy. High-pressure homogenization and ultrasonic emulsification are two of these techniques.28

 

Ultrasonication relies on high-frequency sound waves (20 kHz and higher). They can be employed to create a nano emulsion in situ or to shrink a pre-formed emulsion. Benchtop solicitors are made composed of a piezoelectric probe with an extreme disruptive force at its tip. When ultrasonic waves are dipped in a sample, cavitation bubbles form and expand until they collapse. This implosion generates shock waves, which create a jet stream of surrounding liquid, pressurising dispersed droplets and causing them to shrink in size.29

 

Homogenization under high pressure tremendous-pressure homogenizers provide tremendous energy and uniform flow, resulting in the lowest particle sizes. As a result, high-pressure homogenizers are the most commonly employed to prepare Nano emulsions. High-pressure homogenizers are used to generate powerfully disruptive forces that result in the formation of nano emulsions with extremely small particle sizes (up to 1 nm). Increasing the intensity of homogenization reduces the size of nano emulsion droplets.30

 

2.      Low-Energy Emulsification Methods:

Low-energy emulsification methods, which utilise the system's inherent chemical energy, are often more energy efficient because just basic stirring is required, and they often allow for smaller droplet size than high-energy methods.31

§  Phase Inversion Temperature Method (PIT):

The phase inversion temperature (PIT) method relies on changes in the optimum curvature (molecular geometry) or solubility of non-ionic surfactants with changing temperature. For example, nano emulsions can be spontaneously formed using the PIT method by varying the temperature-time profile of certain mixtures of oil, water and non-ionic surfactant.32

§  Solvent Displacement Method:

Solvent evaporation emulsion is a conventional strategy, with two basic methodologies used for emulsion formation, the preparation of single emulsions, such as oil-in-water (o/w), or twofold emulsions, such as (water-in-oil)-in-water, (w/o)/w. These methods employ high-speed homogenization or ultrasonication, followed by solvent evaporation via uninterrupted magnetic stirring at ambient temperature or under reduced pressure.33

§  Phase Inversion composition Method (PIC):

When ionic surfactants are present, the PIT approach cannot be employed since temperature has no effect on the spontaneous curvature of these systems .The PIC method is a new approach for creating nano emulsions stabilised by anionic surfactants. It entails gradually neutralising a fatty acid with an alkaline aqueous solution added along the emulsification path. As a result, the ensuing fatty carboxylate functions as an ionic surfactant, stabilising the produced nano emulsions34.


 

9.     Methods And Models Used To Evaluate SNEDDS’s.

Method/Model

Information Provided

DLS

Droplet size, PDI, thermodynamic stability

Physico-chemical characterization

Electrophoretic velocimetry

Zeta potential

Spectrophotometry

Transmittance percentage, cloud point, thermodynamic stability

TEM, SEM

Morphology, droplet size

Viscosimeter

Viscosity, thermodynamic stability

Dissolution apparatus

Drug dissolution, emulsification time

Preclinical in vitro and ex vivo evaluation

pH-stat unit

Formulation digestion, drug distribution across aqueous/oil phase

PAMPA

Permeation across intestinal barrier

Preclinical In vivo evaluation

Animals

Pharmacokinetic, toxicity, pharmacodynamic

Clinical trials

Humans

Pharmacokinetic, bioequivalence toxicity, pharmacodynamic

 


10. CONCLUSION:

Given the physicochemical properties of neurotherapeutics, SEDDS have shown a great potential for enhancing drug bioavailability when compared to standard formulations such as tablets, liquids, or suspensions. This is mostly owing to the excipients in SEDDS, which generate nanosized structures after dispersion in aqueous media. The enormous surface area of the droplets generated during aqueous dispersion improves drug solubility, permeability, and absorption via biological mechanisms and improve bioavailability.This happens not only in the GIT following oral treatment, but also when SEDDS are taken via the nasal route. Despite the fact that SEDDS have mostly been investigated for bioavailability augmentation following oral administration, the applicability of SEDDS in nose-to-brain transport warrants more investigation. This is mostly owing to the IN administration route's ability to deliver medications straight to the brain while bypassing the BBB. Thus, compared to the oral method, intranasal administration of neurotherapeutics loaded in SEDDS could result in even better brain bioavailability.

 

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Received on 03.09.2023         Modified on 20.09.2023

Accepted on 29.09.2023   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech. 2023; 13(4):307-314.

DOI: 10.52711/2231-5713.2023.00055