Novel Drug Delivery Systems (Part 2)
By Atish S. Mundada and Alap Choudhari
()
About this ebook
Novel Drug Delivery Systems (Part 2) covers the advanced techniques and innovations transforming pharmaceutical sciences, with a focus on enhancing drug efficacy and patient outcomes. This comprehensive guide explores a wide array of delivery methods, including nasopulmonary, transdermal, ocular, nanotechnology-based, implantable, and controlled-release injectables. Each chapter provides an in-depth analysis of these unique delivery routes, presenting both foundational knowledge and the latest technological advancements in the field.
Designed for students, researchers, and professionals in pharmaceuticals and medicine, this book bridges basic concepts with cutting-edge practices, emphasizing the science and impact of controlled drug delivery.
Key Features:
- Detailed exploration of nasopulmonary, transdermal, ocular, and implantable delivery systems
- Insight into nanotechnology's role in drug delivery
- Comprehensive coverage of controlled-release injectables
Readership:
Ideal for students, researchers, and industry professionals seeking to deepen their understanding of advanced drug delivery methods
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Novel Drug Delivery Systems (Part 2) - Atish S. Mundada
Nasopulmonary Route of Drug Delivery
Bhushan R. Rane¹, *, Akash J. Amkar¹, Ashish S. Jain¹
¹ Department of Pharmaceutics, Shri D. D. Vispute College of Pharmacy and Research Center, Devad-Vichumbe, New Panvel, India
Abstract
Nasopulmonary drug delivery has gained a lot of interest as a convenient, reliable, and promising technique for systemic drug administration. It is especially used for molecules that can only be delivered intravenously and are inefficient when taken orally. This is due to the high vascularization seen above the upper nasal cavity and alveolar region of the pulmonary system, wide surface area, avoidance of first-pass metabolism, gut wall metabolism, and/or destruction in the gastrointestinal tract. Numerous therapeutic compounds may be supplied intranasally for topical or systemic administration. Presently, the nose-to-brain administration route offers targeted delivery. Several further advantages are expected to emerge via the pulmonary route to achieve systemic effects and treat lung disorders. Barriers that prevent absorption through the nasal and pulmonary pathways must be overcome to achieve these therapeutic benefits. Numerous drug delivery devices are being researched for nasal and pulmonary administration of liquid, semisolid, and solid formulations to deliver the medications quickly and/or efficiently to the target area. They are especially suitable for the administration of biotechnological products like proteins, peptides, hormones, and vaccines, as well as poorly soluble drugs, to improve bioavailability. Pulmonary drug delivery has triggered intense scientific and biomedical interest in recent years, and it has made significant progress in the context of local treatment for lung disorders, owing to improved local targeting and fewer systemic adverse effects with the administration of minute therapeutic levels. The chapter attempts to provide some information regarding the nasopulmonary drug delivery system, including the anatomy of the nasal cavity and respiratory tract, the mechanism of drug absorption, characteristics that are considered during the selection of drugs for the nasopulmonary system, factors that affect nasal and pulmonary drug absorption, techniques to improve absorption, dose calculation specifically for intranasal delivery, formulation of dosage forms according to requirement, novel drug formulations, recent improvements of the nasal and pulmonary delivery systems, and some of the patents and commercially also available formulations. The impact of COVID-19 and intranasal vaccine development is discussed in this chapter.
Keywords: Barriers, Inhalers, Mucociliary clearance, Nasopulmonary, Nose-to- brain delivery, Nanoparticles.
* Corresponding author Bhushan R. Rane: Department of Pharmaceutics, Shri D. D. Vispute College of Pharmacy and Research Center, Devad-Vichumbe, New Panvel, India; Tel: +9421534437; E-mail: rane7dec@gmail.com
INTRODUCTION
The nasal mucosa is considered an effective route to deliver drugs for fast absorption and quick entry of drugs into systemic circulation. Nasal therapy, commonly known as NASAYA KARMA
, is a recognized treatment in the Indian medical Ayurvedic systems.
The absorption of the drug is effectively facilitated by utilizing the significant surface area of the nose as a key for the absorption. Villi present on the epithelial surface in the nose are found to be in microns size, known as microvilli, while the layer below the epithelial, called the subepithelial layer, is densely vascularized. Vascularized areas of the nose blood streams immediately make it to the systemic circulation, which fends off the loss of drugs from first-pass metabolism. They offer low doses of drugs and quick attainment of therapeutic levels in the blood. The onset of pharmacological activity is faster and also gives fewer side effects [1-3]. Various notable drawbacks of the nasal route that impact the absorption include a modest volume of application (25-250 µl) and drugs with high molecular weight (˃1000 Da) passing through the nasal mucus layer. Physiological circumstances such as mucociliary drug clearance, enzyme-mediated barriers, and nasal mucosal irritations are also challenges for drug delivery [4-6].
The nasal mucosa is an endothelial basal membrane that is quite thin and porous in comparison to other biological membranes. Stratified squamous epithelium, basement membrane, and lamina propria are the systematic arrangements within the nasal mucosa. The nasal mucosa consists of the epithelium, basement membrane, and lamina propria. The nasal mucosa epithelium predominantly consists of four cells: goblet cells, basal cells, and ciliated and non-ciliated columnar cells [7]. Mucosal secretion is much more aqueous as it is composed of about 95% water, and the other 5% consists of mucin, salts, albumin, lysozyme, immunoglobulin, and lactoferrin, as well as some other proteins and lipids. Some of the antibodies, such as IgE, IgA, and IgG, are also found in the nasal mucus [6]. The epithelial layer is highly vascularized and around 150 cm², with an absorption region featuring microvilli. It also has a quick blood flow. These qualities give it various benefits, including quick drug absorption, quick action, and low overdose risks [8, 9]. There are three mechanisms for drug or therapeutic substances to pass through the nasal mucosa: paracellular, transcellular, and transcytosis [10].
Paracellular transport is associated with tight junctions and intercellular gaps, and it is a considerable pathway, especially for protein and peptide absorption. According to reports, the paracellular pathway should be reversibly open to improve the absorption of peptides by the nasal mucosa. Also, some of the reports state that drug absorption increases by taking up the hydrophilic character of the molecule [11, 12].
Active or passive transport mechanisms are used to achieve the transcellular pathway. It is essential for the absorption of molecules that are acknowledged by the membrane or those that are lipophilic [9].
The mechanism by which a particle is trapped into vesicles and delivered to the cell is called transcytosis. Finally, it gathers in the interstitial space [13].
There are three different routes through the nose for the drug to reach the brain [14]. The olfactory pathway is the very first point of entry for drugs into the brain. Drugs can move to the brain from the olfactory region, which it surpasses through the olfactory epithelium (Consists of basal cells, supporting cells, and olfactory nerve cells) and then promotes to the olfactory bulb via the olfactory nerve. The trigeminal pathway is another route through the nose for the entry of drugs to the brain [15]. In the trigeminal pathway, the drug can get into the brain to achieve nose-to-brain delivery using trigeminal nerves, which innervate the olfactory epithelium and mucosa [16]. The peripheral pathway is the third way to promote brain delivery via the nose (Fig. 1). Drugs are absorbed through the vascular pathways and enter into the systemic circulation by allowing them to bypass the blood-brain barrier (BBB) [17]. Drugs delivered nasally may also reach the lymphatic system and gastrointestinal tract [18].
Fig. (1))
Pathways followed by drug through nasal delivery.
PULMONARY DRUG DELIVERY
Pulmonary drug delivery is effectively capable of therapy with the help of suitable devices known as pulmonary drug delivery (PDD) devices, which have recently been evolved and improved by pharmaceutical industries, lending a hand for its development and also taking steps forward in the management of lung disorders (both local and systemic). PDD devices have a reputation for being able to deliver medications either directly to the body's required site or via the bloodstream to other remote areas. The lungs offer a sizable surface area of alveoli with a dense capillary network, which serves as a remarkable absorption surface for medication administration.
Pulmonary Environment
Gas exchanges within the blood and the surrounding environment, as well as maintaining steady levels of systemic pH, are the primary functions of the lungs that take place in the pulmonary environment. The respiratory system initiates with the trachea, which splits up into the bronchi region. These bronchi divide into tiny bronchi, also called bronchioles, and ultimately develop into terminal (last conducting airway) bronchi that terminate in air sacs called alveoli. The conducting airways are of ciliated columnar epithelium, which approaches the distal airway’s epithelium and becomes cubical. Aerosolized particles get trapped in the serous fluids that line up the bronchial airways, and mucus floats over them. This layer of mucous is continuously moved into the proximal airways through the cilia’s synchronized, rhythmic functioning, where it is taken in or spewed out (MCC). According to reports, a healthy adult patient's peripheral lung has a retention time for particles of about 24 hours [19, 20].
MECHANISM AND PATHWAY OF DRUG ABSORPTION THROUGH PULMONARY ROUTE
Oral inhalation and intranasal administration are the two major primary methods for drug administration through the pulmonary route [21]. The inhalation method is endorsed to attain a homogenous distribution with a great extent of diffusion that reaches the alveolar or peripheral regions of the lungs. Profitable outcomes can be expected with oral inhalation administration because it enables the delivery of small amounts with an average concentration loss of only 20% [22].
Oral inhalation administration includes two methods: intratracheal instillation and intratracheal inhalation. Of these methods, the regularly used technique in investigating or researching areas is intratracheal instillation, which involves the use of a particular syringe to inject a minute amount of drug dispersion or solution into the lungs. For targeted drug deposition, a relatively tiny absorptive region is utilized. As a result, the instillation procedure is considerably simpler and cheaper but causes uneven drug deposition. Preclinical studies suggest that intratracheal instillation is not a physiological mode for administration; it may not be beneficial for aerosol applications in humans [23]. To provide greater and more reliable distribution with significant diffusion, an inhalation technique makes use of aerosolized systems [24].
After the inhalation of an aerosol, a drug particle can enter the pulmonary airway through four main processes: impaction i.e., inertial deposition, sedimentation i.e., gravitational deposition, interception i.e., Brownian diffusion, and electrostatic precipitation. Each of these methods has a different probability based on the features of inhaled molecules, respiring patterns, and behavior of the respiratory system. Although all four mechanisms occur simultaneously, the first is regarded to be the most significant for large molecules in the airways in terms of deposition [25, 26]. After the deposition of particles in the airways of pulmonary systems, drugs are absorbed by transcellular/intracellular [27], paracellular/intercellular [28], and transcytosis/vesicular transport through the lungs [29].
Impaction
When a particle's momentum prevents it from changing directions in a region where the majority of airflow has been altered, then it is said to be impacted (Fig. 2). It functions as the most important deposition mechanism around the airways of the upper region and near the points of bronchial branching. As particle size, breathing frequency, and the velocity of air increase, the impaction also increases [24, 25]. Deposition across various bronchial regions is caused by the inertial impaction that occurs during inhalation, which imparts a centrifugal impact on the particulates [30]. In the upper respiratory tract, impaction is majorly shown by particles larger than µm [31].
Sedimentation
Sedimentation happens when the absolute force of the air obstruction is larger than the gravitational force on tiny particles (Fig. 2). Inhaled particles sediment steadily. The possibility of sedimentation decreases with an increase in breathing rate and is related to both the duration of the particle in the airways and its size. Sedimentation causes an accumulation of smaller particulates of microns size 1-5 within the bronchial region [24, 30].
Fig. (2))
Deposition mechanism followed by drug after administration of an aerosol system.
Diffusion
The Brownian motion of the particles deposits drug particles with smaller sizes of about 2 µm into the alveoli (Fig. 2). Rapid drug particle collisions caused by the particle's random motion lead to drug deposition and diffusion from the alveoli. Deposition by diffusion increases as particle size and flow rate decreases (Table 1). The alveoli region experiences more diffusion deposition because of the small airways and longer residence times [32].
Table 1 Deposition area according to particle size [24].
RATIONALE FOR SELECTION OF DRUG FOR THE NASOPULMONARY DELIVERY
Ideal Characters for Selection of Drug for Nasal Delivery
Characteristics that need to be considered for the assortment of a drug to develop a product for delivery through the nose include the following: The drug should not irritate the nasal mucosa, it should not have any side effects, the drug should not contain any toxic metabolites, it should not have any offensive odors, and most importantly, the drug should have a suitable nasal absorption property [33]. Some of the parameters that need to be considered for selection are discussed below (Table 2).
Table 2 Parameters consideration for selection of drug for nasal route.
Ideal Characteristics for Selection of Drug for Pulmonary Delivery
Drug characteristics that need to be taken into account for delivery through the pulmonary route include the particle size of the drug that targets the site of absorption, which should be in the range of 1 to 5 microns [34]. Drugs should have low oral bioavailability because high oral bioavailability might reduce the amount of consumed drug that is bioavailable and negatively affect airway selectivity, raising the risk of systemic side effects. To effectively treat pulmonary conditions, inhaled medications should have higher airway selectivity and have a better target in the pulmonary region [35].
FACTORS INFLUENCING DRUG ABSORPTION
Factors Affecting Absorption of Drug through Nasal Route
Numerous aspects affect the systemic biological availability of drug discharge via nasal administration. Anatomical and physiological conditions of the nasal cavity, nasal drug delivery system’s features, and physicochemical properties of the drug can all have an impact on the rate at which a substance is absorbed. The nasal bloodstream, the nasal cycles, the valve of the nasal and their aerodynamic nature also, the nasal and sinus vasculature and lymphatic system, mucociliary clearance, the transporter and efflux system, and enzymatic degradation are the various barriers to the absorption of substances through the nasal route [36]. For most drugs to achieve therapeutically appropriate blood levels following nasal administration, several factors are necessary [37].
Drug Physicochemical Considerations
Molecular or Particle Size
The permeability of drugs and molecular weight are inversely correlated with water-soluble compounds, whereas they have a direct correlation with lipophilic drugs [37]. The molecular size has a noteworthy outcome on the penetration rate [38, 39].
Lipophilic-Hydrophilic Balance
The compound's natural absorption via nasal mucosa increases with increasing lipophilicity. Although certain hydrophilic features of the nasal mucosa were recognized, the mucosal membrane of the nasal route is found to be lipophilic, thus, the lipoidal nature of the membrane is a vital factor as a barrier for absorption [40, 41].
Enzymatic Degradation in Nasal Cavity
In the nasal cavity, proteins and peptides are absorbed poorly. Therefore, when these drugs pass via the nasal epithelial barrier or the nasal cavity lumen, they may be vulnerable to enzymatic drug molecular degradation [42].
Nasal Effect
Membrane Permeability
Water soluble drugs, particularly drugs that have a high molecular weight, for example, proteins and peptides, eventually comprise the lightest penetration ability in the membrane. As a result, the endocytosis transport system is mostly responsible for the absorption of a small number of proteins and peptides [43, 44].
Environmental pH
According to the studies, rat’s nasal absorption of small water-soluble substances like alkaloid acid, benzoic acid, and salicylic acid occurred most frequently at pH where described substances are in the non-ionized state. This may perhaps manifest that the non-ionized lipoid form passes across the barrier of nasal epithelium via the transcellular pathway, while most ionized lipoid forms move via the aqueous paracellular route [45].
Mucociliary Clearance
Nasal mucociliary clearance is a crucial division governing the delivery of drugs and vaccines by nasal route. Mucociliary clearance helps to prevent non-toxic substances. Because of the slope that the nasal cavity has in its direction toward the pharynx, the anatomy supports this clearance [46].
Cold, Rhinitis
The common disease rhinitis, which frequently occurs, affects the drug's bioavailability. Common symptoms include excessive secretion, itching, and sneezing, which are typically brought on by viruses, germs, or irritants. It is mostly characterized as allergic rhinitis. This condition is mostly caused by acute or else chronic irritation, redness, swelling, and soreness of the nasal mucous. Inflammation caused by the disorders interferes with drug absorption through the mucous membrane [45].
Delivery Effect
Formulation (Concentration, pH, Osmolarity)
The mechanism by which a substance is absorbed or permeates through the nasal membrane depends heavily on the concentration gradient. As an example, nasal perfusion studies show a decrease in salicylic acid absorption with concentration. This decrease is probably caused by irreversible injury within the mucosal membrane of the nose [37, 47].
To reduce nasal irritation, the pH of the nasal preparations ought to be in the range of 4.5-6.5, and the nasal formulation’s pH has to be in the range of 4.5-6.5, which also improves penetration and inhibits bacterial growth [48, 49].
The absorption of drugs through the nasal route is impacted by the osmolarity of the prepared dosage form, which was determined from a study of rats. Nasal absorption is influenced by the formulation's sodium chloride concentration. The maximum absorption was attained at a concentration of 0.462 M sodium chloride; a greater concentration results in increased bioavailability and also increases toxicity to the epithelium of the nose [50].
Deposition and Drug Distribution
The distribution of drugs inside the nasal cavity is a decisive aspect that affects the absorption of the drugs. Drug distribution in the nasal cavity, which helps to determine the drug absorption, may depend on the way the medication is administered. The site of disposition largely determines the nasal dosage forms' absorption and bioavailability. The anterior part of the nasal region gives an extended nasal residence period for formulation disposition, which enhances drug absorption. Additionally, the dosage form can be deposited into the cavities of the nose; however, as nasal mucociliary clears off, the deposited dosage forms might show low bioavailability [37, 51].
Viscosity
The duration of drug interaction with the nasal mucosa rises as formulation viscosity increases, which lengthens the time it takes for its permeation. Furthermore, very viscous formulations customize drug permeability by obstructing the regular process, like ciliary beating and mucociliary clearance [37].
Factors Exert Influence on Absorption through the Pulmonary Route
Factors that impact the absorption of drugs through the pulmonary route are physiological factors and pharmaceutical factors, which affect particle depositions. Physiological factors consist of the morphology of lungs, inspiratory flow, aerosol coordination with inhalation, tidal volume, and disease conditions, as well as mucociliary escalation, macrophage phagocytosis, and translocation into lymph, blood, and cells. Pharmaceutical factors are aerosol velocity, size and shape, density, and physical stability. These factors are related to the barriers of the pulmonary route described below:
Mechanical Barrier
A sophisticated system of airway tissues found in the lungs is known as the bronchial tree. The numerous airway bifurcations may take in a particle that makes its way through the alveolar region of the to the targeted sites of the epithelial area [52]. In pathological situations, due to inflammation, bronchi constriction, or mucous hypersecretion, the airway narrows and increases the mechanical barrier of the pulmonary region. By clearing the accumulated particles from the airways, lung mucociliary clearance also provides important mechanical barrier properties [53-55].
Chemical and Immunological Barrier
Drugs that are deposited in the pulmonary airways may be affected by substances such as surfactants and proteolysis enzymes (proteases). Proteins and peptides in the lungs may be hydrolyzed by enzymes that are proteolytic such as cathepsin H and neutral endopeptidase, making them inactive [52]. Drug particles that are not dissolved might come in contact with alveolar macrophages, which serve as the primary phagocytotic cells shielding against inhaled molecules. Alveolar phagocytes form an immunological barricade, which makes them unable to distinguish between substances that might be potentially harmful and those that might be beneficial. Drug metabolites may be absorbed by macrophages and expelled through the lungs, possibly by way of the lymphatic systems or else by pushing toward the bottom of the mucociliary region [56, 57].
Behavioural Barrier
Adherence
The use of inhaler devices by patients has a significant impact on how well drugs are delivered into the lungs [58]. A number of doses taken, stated in terms of the number of doses prescribed, might be used to define adherence [59]. The patient’s behavioral characteristics cause an impact on the effectiveness of the therapy, such as intentional or unintentional non-adherence to the prescribed routine therapy [60].
Inhaler Technique
The distribution of inhaled drugs is known to be hindered by poor inhaler technique [61]. One of the common mistakes in the inhaler process for pMDIs is failing to inhale deeply and gently and failing to activate the inhaler at the same time as breathing in (poor conditions). Most typical issues with DPIs include improper device orientation, inadequate inhalation force, and errors in device-specific handling and preparation. The majority of nebulizers can be used with relaxed tidal breathing; however, some patients still mishandle them during their use and do not assemble them properly [52].
STRATEGIES TO IMPROVE ABSORPTION
Strategies or Techniques to Improve Nasal Absorption
Several strategies are used to enhance the drug’s bioavailability through the nasal mucosa, including prolonging the period of nasal residence of the drug, improving absorption through the nose, and modifying the structural arrangements of the drug to change its physicochemical properties.
Nasal Enzyme Inhibitors
Enzyme inhibitors can inhibit drug metabolism in the nasal cavity. This approach is mostly for the improvement and development of the formulation of peptides and protein molecules through the nasal route [62].
Permeation Enhancers
Permeation enhancer’s primary objective is to increase the drug absorption. The rate at which the drug penetrates the mucosal membrane is enhanced using absorption enhancers. Several enhancers alter the epithelial cells’ structure in some way, but they must avoid causing the nasal mucosa to become damaged (Table 3) [37].
Table 3 Different types of chemical penetration enhancers and their examples [63].
Prodrug
The strategy of a prodrug is primarily intended to maximize beneficial physicochemical characteristics, including solubility, taste, odor, stability, etc [64]. Prodrug, sometimes known as pro-moiety, is a medication used to mask undesirable functional groups with favorable functional groups [65].
Particulate Drug Delivery System
The importance of particle design in improving absorption is becoming essential. Active medicine can be included in microspheres, nanoparticles, or liposomes, among other delivery vehicles [66]. To increase treatment efficacy, they can have a variety of different properties. Overall, this may lead to an improvement in the stability and effectiveness of absorption as well as a decrease in the toxicity of the active substance [62].
Bio-adhesive Polymer for Delivery from Nose to Brain
Innovative methods for keeping the medication at the absorption site are presented. These techniques can be effective for active targeting in the olfactory region with controlled release and bio-adhesion properties. It has been observed in research studies that after administration, the gel of pectin persists in the nasal cavity. Chitosan (Obtained from chitin) is renowned for its abilities as a bio-adhesive and an absorption enhancer. A technique has been proposed that merges bio-adhesive preparations with an intermediate host that specifically targets the receptors on the olfactory region, along with absorption enhancers that might target the site and also detain the preparation on the absorption site for an extended period, as well as increase the transport through the membrane with transcytosis, for example, receptor-mediated or paracellular mechanisms [37, 67].
Strategies to Improve Pulmonary Absorption
Molecular Modification
Decreasing Dissolution Rate and Solubility
Following inhalation, drugs that are water soluble might readily dissolve in lung lining fluid, diffuse through the epithelium of airways, and be absorbed from the lungs [68]. However, a weak water-soluble material may prevent sufficient disintegration of the inhaled medication particles due to the inadequate volume of fluid in the lung lining [69]. Several medications that are poorly