A Review on Pulmonary Drug Delivery System

 

Patidar S., Mandloi R., Pillai S., Birla N.

GRY Institute of Pharmacy, Borawan (Khargone) M.P. India.

*Corresponding Author E-mail: sagarpatidar398@gmail.com

 

ABSTRACT:

Now a day’s pulmonary drug delivery remains the preferred route for administration of various drugs. Pulmonary drug delivery is currently the focus of accelerated research and development because of the potential to produce maximum therapeutic benefit to patients by directly targeting drug to the site of pathology in the lungs. These routes of drug delivery may give the advantages like a small amount of drug, less adverse reaction and rapid onset of action. Drug delivery by the pulmonary route has evolved to be one of the most widely used systemic or local drug delivery approach. Recent progress within biotechnology has generated a group of novel protein and peptide drugs to which administration to the respiratory tract, to obtain systemic delivery seems advantageous compared to e.g. parenteral or gastrointestinal administration (tablets, capsules etc.). A successful pulmonary administration requires a harmonic interaction between the drug formulation, the inhaler device, and the patient. The delivery device plays a major role in the efficiency of pulmonary delivery, and great strides have been made in the development of new devices in recent years. The devices most commonly used for respiratory delivery, including nebulizers, metered-dose inhalers, and dry powder inhalers. the choice of device will depend on the drug, the formulation, the site of action, and the pathophysiology of the lungs. Pulmonary drug delivery system has been widely used in various diseases conditions like asthma, COPD, angina pectoris, diabetes, cancer, migraine, tuberculosis, acute lung injury and other.

 

KEYWORDS: Pulmonary drug delivery, drug deposition, drug delivery carriers, drug delivery devices, applications.

 

 


INTRODUCTION:

Pulmonary drug delivery system has been widely used for the treatment of lung diseases and is acclaimed for the asthma Treatment and chronic obstructive pulmonary diseases. This System is a needle free technique. But administration of drug by this route is Technically challenging because oral deposition can be high, and Variation inhalation techniques may affect the quantity of the Drug delivered to the lungs.

 

Delivery of locally acting drugs to the Site of action reduce the amount of dose needed to produce the Pharmacological action but now the lungs have been studied as A possible route to administer the treatment of systemic disease Like diabetes mellitus, angina pectoris, cancer, bone disorders, Migraine, tuberculosis, acute lung injury and others. Pulmonary Delivery is apprehended by various ways like aerosols, Metered Dose inhaler systems (MDIs), Dry powder inhalers (DPI) And Nebulizers. These types of system may contain Nano Formulations like micro emulsions, micelles, bio-degradable Nanoparticles and liposomes. [1] Millions of people are affected by pulmonary diseases and their populations are continuously increasing worldwide. These include chronic obstructive pulmonary disease (COPD), tuberculosis, lung cancer, cystic fibrosis, Pulmonary hypertension, asthma and various others which Are complex human airway disorders. [2] The primary goal of inhalation therapy for local treatment is to reduce pulmonary symptoms, for example, Through the alleviation and/or prevention of airway inflammation and constriction. Typical examples of inhaled drugs are corticosteroids, beta-sympathomimetic, Muscarinic antagonists, and antibiotics. The inhalation of these drugs offers substantial benefits over their systemically administered formulations. [3]

 

Advantages:

1    It provides a non-invasive Method of delivering drugs into The bloodstream for those Molecules that currently can only Be delivered by injection. These Include peptides and proteins, such as insulin for diabetes or Interferon beta for multiple Sclerosis and most of the drugs Developed in recent years by Biotechnology companies.

2    Allow efficient drug targeting to the lungs for relatively common Respiratory tract diseases such as Asthma, emphysema, and chronic, Bronchitis.

3    It gives very fast onset of action Comparable to the i.v. Route and Quicker than can be achieved with either oral delivery or Subcutaneous injections.

4    Inhaling helps to avoid Gastrointestinal tract problems Such as poor solubility, low Bioavailability, gut irritability, Unwanted metabolites, food Effects and dosing variability.

5    It requires low and fraction of Oral dose i.e. drug content of one4 mg tablet of salbutamol equals to 40 doses of meter doses.

6    Pulmonary drug delivery having Very negligible side effects since Rest of body is not exposed to Drug.

7    In asthma and diabetes require Long term treatment if it is given by pulmonary drug delivery Safety is maximum because rest of body not exposed to drug. [4]

 

Disadvantages:

1.     Improper dosing.

2.     Stability of drug in vivo.

3.     Some drug may produce irritation and toxicity.

4.     Difficulty in producing optimum particle size.

5.     Some drugs may be retained in lungs and clearance of the drug may be difficult.

6.     Targeting specificity.

7.     Difficult to transport.

8.     Difficult to use.

9.     Drug absorption may be limited by the physical barrier of the mucus layer. [5]

 

Mechanisms involved in deposition of particles in lungs:

The deposition of inhaled particles in the different regions of the respiratory system is very complex, and depends on many factors. Some of the factors influencing respiratory deposition include:

·       Breathing rate

·       Mouth or nose breathing

·       Lung volume

·       Respiration volume

·       Health of the individual

·       Bifurcations in the airways result in a constantly changing hydrodynamic flow field.

 

Depending on the particle size, airflow, and location in the respiratory system, particle deposition occurs via on of the Following principal mechanisms. [6]

 

Impaction:

Impaction of particles in the respiratory system is due to inertia of particles. The probability of particle deposition by impaction is related to the mass of the individual particle i.e. size and density and on the particle’s travelling velocity, which is determined by the respiratory flow velocity prevailing in the airways.

 

Sedimentation:

Sedimentation is the settling out of particles in the smaller airways of the bronchioles and alveoli, where the air flow is low and airway dimensions are small.

 

Interception:

Interception occurs when a particle contacts an airway surface due to its physical size or shape. Unlike impaction, particles are deposited by interception do not deviate from their air streamlines.

 

Diffusion:

Diffusion is the primary mechanism of deposition for particles less than 0.5 microns in diameter and is governed by geometric rather than aerodynamic size. Hence, the highest probability of particle deposition due to diffusional displacement occurs for very small particles inhaled into the lung periphery with its small airway dimensions. [7]

 

Absorption:

The pulmonary membrane is naturally permeable to small molecule drugs and to many therapeutic peptides and proteins. The epithelium of the lung, the significant barrier to absorption of inhaled drugs, is thick (50–60 μm) in the trachea, but Diminishes in thickness to an extremely thin 0.2 μm in the alveoli. [6]

 

Factors affecting pulmonary drug delivery:

Mechanisms of Particle Deposition in the Airways:

Effective resistance mechanisms may have Involved may reduces the burden of external particles Enter the airways, and clearing those it may achieve Something in being stored. Therapeutic aerosols are Two-phase colloidal systems in that the drug is Contained in a dispersed phase they may have a solid, Liquid or combination of the two, based on the Method and formulation of aerosol generation.

 

Inertial impaction:

This is the main deposition mechanism for Particles >1 μm in the upper s at an airway branching site Impaction it mainly occurs near the bifurcations, Certainly the impaction of particles from tobacco Smoke on the bifurcations may be one cause why These sites are often the foci for lung tumors.

 

Description of particle deposition mechanisms at an airway branching site:

Impaction it mainly occurs near the bifurcations, Certainly the impaction of particles from tobacco Smoke on the bifurcations may be one cause why These sites are often the foci for lung tumors.

 

Sedimentation:

By the settling under gravity the particles may Deposited. It becomes highly important for particles That reach airways where the airstream velocity is Relatively low, e.g. the bronchioles and alveolar Region.

 

Brownian diffusion:

This is of minor significance for particles >1 μm. Particles smaller than this size are displaced by a Sequentially bombardment of gas molecules, which May result in particle collision with the airway Walls. The chances of particle deposition by diffusion Increases with the particle size decreases.

 

Physiological Factors Affecting Particle Deposition in The Airways:

 

Lung morphology:

Each successful production of the Tracheobronchial tree produces airways of falling Diameter and length.

 

Inspiratory flow rate:

When the inspiratory flow rate increases they Enhance deposition by impaction in the first few Generations of the TB region.

 

Co-ordination of aerosol generation with Inspiration: The energy of aerosol particles generated from Pressurized metered dose inhalers (p MDIs, is largely Govern by the pMDI formulation rather than the Subject’s IFR. pMDI aerosol droplets will be Travelling at velocities of 2,500–3,000 cm s−1.

 

Tidal volume:

An increased IFR will usually be connected with an enlarge in the volume of air inhaled in one breath, The tidal volume. Obviously an increase in tidal Volume will result in penetration of aerosol particles Deeper into the TB and A regions and a better chance for deposition inside these regions.

 

Breath holding:

Increasing the time between the end of Inspiration and the start of exhalation increase the Time for sedimentation to occur. Breath-holding is Normally used to optimize pulmonary drug delivery.

 

Disease states:

Bronchial obstruction as seen in different Pulmonary disorders may associated with the larger Local airflows and turbulence and this will result in Localized deposition in the larger airways of the Trachea-bronchial region.

 

Pharmaceutical factors affecting aerosol deposition:

Aerosol velocity:

pMDIs Generate aerosol droplets with velocities greater than the inspiratory airflow and therefore the aerosol will Have a greater affinity to impact in the oropharyngeal Region.

 

Size:

Marketable devices do not lead to monodispersed Particles and frequently the size distribution is Extensive and the particles may show varying shapes.

 

Density:

Particles having densities less than 1 g cm−3 (unit Density) may have a mean physical diameter larger Than the aerodynamic limit.

 

Physical stability:

The high humidity environments of the airways, may Enlarge in size and thus have a greater chance of Being prematurely deposited. It be supposed to not be Assumed, however, that the uptake of water vapor Will always occur. [8]

 

Drug delivery carriers for pulmonary delivery:

Drugs for pulmonary delivery require some carriers for Targeted action in lungs. Carriers may help in reducing the Side effects also. The carrier systems used for pulmonary Drug delivery are given below [9]

 

Liposomes:

Liposomes are a form of vesicles that consist either of Many, few or just one phospholipid bilayers. The polar character of the liposomal core enables polar drug molecules to be encapsulated. Amphiphilic and lipophilic molecules are solubilized within the phospholipid bilayer according to their affinity towards the phospholipids. [10] A typical liposome consists of a single bilayer lipid membrane (unilamellar liposomes) or several bilayer lipid membranes (multilamellar liposomes). [11]

 

Biodegradable polymers:

There is a world-wide research effort to develop Biodegradable polymers as a waste management option for Polymers in the environment. Biodegradation (i.e., biotic Degradation) is a chemical degradation of materials (i.e. Polymers) provoqued by the action of microorganisms such as bacteria, fungi and algae. The most popular and important biodegradable polymers Are aliphatic polyesters [e.g., polylactide, poly(ε-caprolactone), polyethylene oxide, poly(3-hydroxybutyrate), polyglycolic acid] and thermoplastic proteins. [12]

 

Large porous Particles:

pulmospheres are the new type of aerosol formulation is the large Porous hollow particles, they have low particle densities, excellent Dispensability and can be used in both MDI and DPI delivery systems. These particles can be prepared using polymeric or non-polymeric Excipients, by solvent evaporation and spray‐drying techniques. Pulmospheres are made of phosphatidylcholine, the primary Component of human lung surfactant. [3]

 

Nano particles and nano suspensions:

Suspensions of water-insoluble drugs become increasingly important for miniaturized liquid nebulizers (soft-mist Inhalers). For both topical and systemic administration Through the lungs, Nano particulate formulations (typical size Between 100 and 700 nm) offer several important advantages Over the more traditional micro suspensions (size between 1And 5 mm). As discussed earlier, nanoparticles can afford Higher bioavailability, which is attributable to more efficient Drug delivery, more rapid dissolution or increased residence Time in the lung. [13]

 

Lactose carrier system:

Lactose is the most common and frequently used Carrier in DPI formulations accordingly nowadays Various inhalation grades of lactose with different Physico-chemical properties are available on the Market. The advantages of lactose are its well Investigated toxicity profile, physical and chemical stability, compatibility with the drug substance, its broad availability and relatively low price. α-lactose monohydrate is the most common lactose grade used in the inhalation field. Almost all DPI formulations on the market are based on α-lactose monohydrate as a carrier. [14]

 

Dendrimers:

Dendrimers (also known as dendritic polymers) are nanoparticles that resemble a series of Tree-like branches surrounding a central core an inner dendritic constitution of extremely Branched polymers, and an exterior of multivalent functional groups. The multifunctional surface shell and hyper-branching tree-like interior with cavities facilitate Conjugation or encapsulation of drug molecules.

 

Polymeric Micelles:

The polymeric micelles represent a potential Nano carrier for the efficient delivery of Anticancer agents. A polymeric micelle is principally formed when the hydrophobic part of the block copolymer is driven to the interior, which can encapsulate a poorly soluble drug, Whereas the hydrophilic portion of the block copolymer faces outward to form the shell. Most Micelles are made up of amphiphilic polymers such as polyethylene glycol (PEG) and Polyethylene oxide (PEO), which are FDA-approved excipients. Gill et al produced Polyethyleneglycol (PEG) 5000–di-stearoyl phosphatidylethanolamine (PEG5000–DSPE) Micelles bearing paclitaxel through solvent evaporation technique. [11]

 

drug delivery devices:

Pressurized mastered dose inhaler:

A metered dose inhaler is a drug delivery system that Produces a medicament in the form of fine having Aerodynamic particle size of less than 5 microns for direct Inhalation to the airways. It is used for the treatment of Respiratory diseases such as asthma and COPD. These Devices can be categorized into two types such as: accurately Metering devices (e.g. spray pumps, pressurized metered Dose inhalers (pMDIs), Unit/Bi-doses) and non or poorly Metering devices. [2]

 

Advantages of Pmdi:

1.     It delivers a specified amount of dose.

2.     It is small in size, portable and convenient for use.

3.     It is usually less expensive as compared to dry powder inhalers and nebulizers.

4.     Quick to use.

5.     The contents are protected from contamination by pathogens.

6.     It is having multi-dose capability more than 100 doses available.

 

Disadvantages of Pmdi -

1.     It is difficult to deliver high doses through pMDI.

2.     Accurate coordination between actuation of a dose and inhalation is required.

3.     Drug delivery is dependent on patient technique. [15]

 

Dry Powder Inhalers (DPIs):

DPIs are devices that deliver the medicament as the dry powdered formulation of the active sub-Stance for local and systemic effect via the pulmonary route. These devices have proved deep Lung penetration by the amalgamation of the performance of the device and powdered formulation. DPIs depend on the patient’s inspiratory flow rate; Thus devices are developed by taking into consideration children, patients with decreased lung function due to age or disease. [16]

 

The principle of dry powder inhaler is given below –

 

Unit-Dose Devices:

Single‐dose powder inhalers are devices in which a powder containing capsule is placed in a Holder. The capsule is opened within device and powder is inhaled. It consists of,

 

Rotahaler:

Insert a capsule into the rotahaler, the colored end first, twists the rotahaler to break the Capsule. Inhale deeply to get powder into the airway.

 

Spinhaler:

It works similar to rotahaler, except that outer sleeves slide down to pierce the capsule and Propellant disperse the drug.

 

Multi-dose Devices:

The multi-dose device uses a circular disk that contains either four or eight powder doses on a Single disk. It consists of,

 

Turbohaler:

It is a dry powder inhaler available in an easy to use format. It can overcome the need for Both a carrier and loading individual doses. [5]

advantages of DPI are as follows;

1.     High drug dose carrying capacities Range from less than 10mg to More than 20 mg.

2.     Minimal extra pulmonary loss of Drug due to low oropharyngeal Deposition, low device retention and low exhaled loss.

3.     Less potential for extractable from Device components. [17]

 

Nebulizer:

Nebulizers are medical devices that convert liquid drug into Aerosols or fine mist of minimal size which can be easily Inhaled so that it directly reaches the inferior part of the Respiratory tract, through a facemask or mouth piece. A Nebulizer can be used with an electrical compressor, which Vaporizes drugs so that they can be inhaled to open out the Airways, or it can use an ultrasound crystal that vibrates. Mesh nebulizers use a new type of technology which forces Liquid medications through a mesh, which has multiple Apertures, in order to generate fine mist or aerosol. [18]

 

Types of Characteristics:

Nebulizers can be characterized as:

A) Jet Nebulizers:

Traditionally, jet nebulizers have been used for the treatment of pulmonary diseases. Jet nebulizers are effective in delivering formulations that cannot be delivered with pressurized Metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs). For instance, antibiotics, mucolytics, Liposomal formulations, and recombinant products, such as Pulmozyme® Inhalation Solution, are Some of the medications that can be delivered via jet nebulizers. Jet nebulizers are divided into four categories: (1) jet nebulizers with a corrugated tube, (2) jet nebulizers with a collection bag, (3) breath-enhanced jet nebulizers, and (4) breath-actuated jet nebulizers. [19]

 

B) Ultrasonic Nebulizers:

Ultrasonic nebulisers are mostly preferred for aerosol therapy as They have a greater output capability than air jet nebulisers. The generation of aerosolized particles is through high frequency ultrasonic Waves while the vibration required is within the range of (1.2–2.4 MHz) Of a piezo-electric crystal. The smaller droplets are stored Inside the chamber of the nebulizer which is inhaled by the patient. In Contrast with the jet nebulizer the residual mass which is confined in The nebulizer device, but the advantage of vibration mechanism overcomes the leakage as there is no gas source involved in the delivery of Aerosol.

 

C) Mesh Nebulizer:

Mesh nebulisers can be used to deliver the liquid drug formulations as well as suspensions; however, in case of suspensions performance Seems to be reduced with respect to the mass of inhaled aerosol and the Output rate. Result of in vitro studies suggested that marketed mesh Nebulisers reduce the nebulization time without affecting the efficiency of drug. [20] New nebulisers based on mesh technology have Recently been introduced into the market. They Can operate with batteries and are small enough to be carried. They are efficient, silent and comply with active drug compounds. Mesh nebulisers can be classified into two types: static mesh and vibrating mesh nebulisers. The Characteristics of several different mesh nebulisers.

 

Static Mesh Nebulisers:

Static mesh nebulisers apply a force on the liquid drug to push it through a static mesh. Which can then be inhaled directly by the Patient. Unlike jet and ultrasonic nebulisers, the Aerosol is not recycled in the mesh nebuliser. Droplets generated through the mesh have a~3 µm, which are produced by electroplating The Micro air® NE-U22V can nebulise aqueous solutions and suspensions. It can be loaded with a maximum volume of 7ml.

Vibrating Mesh Nebulisers:

Vibrating mesh nebulisers use mesh deformation or vibration to push the liquid drug through the Mesh. An annular piezo element, which is in contact with the mesh, is used to produce vibration around the mesh, and the liquid Drug is in direct contact with the mesh. Holes in the mesh have a conical structure, with the Largest cross-section of the cone in contact with the liquid drug, which can be inhaled by the patient. The Aeroneb® Go is a vibrating mesh nebuliser (Nektar Therapeutics, San Carlos, CA, USA), Which utilises a horizontal mesh containing 1,000 holes obtained by electrolysis, and Vibrates at 100 kHz. It can be loaded with a maximum volume of 6ml. [21]

 

Current Applications of Pulmonary Drug Delivery System [22]

·       Application of pulmonary drug delivery in Asthma and COPD.

·       Recent role pulmonary delivery in Patients on ventilators

·       Pulmonary delivery in cystic fibrosis

·       New use of pulmonary delivery in Diabetes

·       In migraine

·       Angina pectoris

·       Role of pulmonary delivery in vaccination

·       In emphysema

·       Recent use of pulmonary drug delivery in Transplantation

·       In Pulmonary arterial hypertension

·       In acute lung injury

·       Application of pulmonary drug delivery as a surfactant aerosol

·       Gene therapy via pulmonary route

·       Application of pulmonary drug delivery in cancer chemotherapy

·       Delivery of pentamidine by pulmonary Route

·       Delivery of Amphotericin by pulmonary Route

·       Delivery of Gentamycin by pulmonary Route

·       Nicotine aerosol for smoking cessation

·       Inhaled drug delivery for tuberculosis Therapy

 

Future scope:

A Cross-Section of current research in the field of pulmonary drug delivery is published. There is still a lot of work to be done in the areas of inhaler devices and formulation development, particularly, with regards to dry powder and colloidal systems. A severe limitation in this field of research is the small number of excipients FDA/EMA-approved for inhalation. Topical delivery of antibiotics appears to be an area that has attracted a lot of interest in recent years and is likely to make an even bigger impact in the treatment of pulmonary infections in the future. Moreover, viral lung diseases such as COVID-19 are a challenge and delivering antivirals by inhalation might be an approach worth considering. In addition to infectious diseases, conditions such as lung cancer are being actively researched in the context of inhalation drug delivery. The respiratory route can also be utilised to achieve mucosal vaccination against bacterial or viral infections. [23]

 

CONCLUSION:

The lung has served as a route of drug administration for thousands of years. Now a day’s pulmonary drug Delivery remains the preferred route for Administration of various drugs. Pulmonary drug Delivery is an important research area which impacts the treatment of illnesses including asthma, chronic Obstructive pulmonary disease and various diseases. Inhalation gives the most direct access to drug target. In the treatment of obstructive respiratory diseases, Pulmonary delivery can minimize systemic side Effects, provide rapid response and minimize the Required dose since the drug is delivered directly to the conducting zone of the lungs. It is a needle free Several techniques have been developed in the recent Past, to improve the Quality of pulmonary drug Delivery system without affecting their integrity. Because of advancement in applications of Pulmonary drug delivery it is useful for multiple Diseases. So pulmonary drug delivery is best route of Administration as compare to other routes.

 

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Received on 20.12.2020         Modified on 29.12.2020

Accepted on 03.01.2021  ©AandV Publications All right reserved

Res. J. Pharmacognosy and Phytochem. 2021; 13(1):44-50.

DOI: 10.5958/0975-4385.2021.00008.X