ABOUT AUTHORS:
Dr. N.V. Satheesh Madhav, Girish Dwivedi*
Dehradun Institute of Technology, Faculty of Pharmacy
Village Makkawala, Mussoorie Diversion Road,
Dehradun-248009
*Girish10.dwivedi@yahoo.com
ABSTRACT
Pulmonary route of drug delivery gaining much importance in the present day research field as it enables to target the drug delivery directly to lung both for site specific and systemic treatment. The review is prepared with an aim to discuss about the technical, physiological, and efficacy aspects of the novel pulmonary route of drug targeting and different delivery devices such as metered dose inhalers (MDI), dry powder inhalers (DPI), nebulizers, etc. The review also focuses on the mechanisms of pulmonary drug administration along with compatibility of the excipients employed, devices used, techniques of particulate dosage production, evaluation and advancements in the pulmonary drug delivery. It can be concluded from whole study that different pulmonary delivery system possesses certain specificity for dosage formulations and serves as an important tool to deliver drugs to the target site.
REFERENCE ID: PHARMATUTOR-ART-1700
INTRODUCTION
The delivery of the drug through the respiratory tract is called pulmonary drug delivery. In case of brochodialating drugs, this is advantageous as drug will deliver directly to region where its action is required so that the drug effect will be faster and low dose of drug can be administered through this delivery system and so the side effects can be decreased.
Drugs like sodium carmoglicate are absorbed to less extent when given orally. And some other drugs like isoprenaline is metabolized in the liver. These types of drugs can be administered through pulmonary route.
Pulmonary route have been used to treat various respiratory diseases for centuries. Ancient inhalation therapies included the use of leaves from plants, vapors from aromatic plants, balsams, and myrrh. However, around the turn of the 19th century, with the invention of liquid nebulizers, these early treatments developed into legitimate pharmaceutical therapies.
In the 1920 s adrenaline was introduced as a nebulizer solution, in 1925 nebulizer porcine insulin was used in experimental studies in diabetes, and in 1945 pulmonary delivery of the recently discovered penicillin was investigated. steroids had been introduced in the mid 1950s for the treatment of asthma and nebulizers were enjoying widespread use. In 1956 the pressured metered dose inhaler (pMDI) was introduced, over the past 5 decades, helped by the advances in molecule design and drug discovery the pMDI has risen to become the main stay of asthma treatment. Over the decade certain drugs have been sold in compositions suitable for forming drug dispersion for pulmonary delivery to treat various conditions in humans. Such pulmonary drug delivery compositions are designed to be delivered by inhalation by the patient of a drug dispersion so that the active drug within the dispersion can reach the lung. It has been found that certain drugs given by pulmonary route are readily absorbed through the alveolar region directly into blood circulation. Pulmonary route possesses many advantages over other routes of administration for the treatment of specific disease states, particularly lung associated large protein molecules which degrade in the gastrointestinal conditions and are eliminated by the first pass metabolism in the liver can be delivered via the pulmonary route if deposited in the respiratory zone of the lungs systemic delivery via the lung offers advantages that Supply drugs into the bloodstream directly. It allows for those molecules that currently can only be delivered by injection. Growing attention has been given to the potential of a pulmonary route as an non-invasive administration for systemic delivery of therapeutic agents (mainly peptides and proteins) due to the fact that the lungs provides an big surface area through which molecules can be absorbed and goes direct into the bloodstream. The conducting airways branch 12–23 times and their surface area measures approximately 0.8m.sq.In adults could provide a large absorptive surface area (up to 100 m2 ) but extremely thin (0.1 μm – 0.2 μm) absorptive mucosal membrane and good blood supply. However, recent advances show great promise, but pulmonary delivery of peptides and proteins is complicated by the complexity of the anatomic structure of the human respiratory system and the effect of disposition exerted by the respiration process.
The efficacy of a treatment mostly depends on the techniques by which the drug is delivered and optimum concentration of the drug, above or below this range can be toxic or produce no therapeutic benefit at all. The slow progress in the efficacy of the treatment of severe diseases, has suggested a growing need for a multidisciplinary approach to the delivery of therapeutic agents to targets in tissues. The efficacy of the drug and its treatment can be achieved from the new ideas on controlling the pharmacokinetics, pharmacodynamics, immunogenicity, and biorecognition. These new strategies based on interdisciplinary approaches such as polymer science, pharmaceutical technology, bioconjugate chemistry, and molecular biology, are often called novel/advanced drug delivery systems. Different drug delivery/drug targeting systems already exist and currently under development can be efficiently used to minimize the drug degradation and loss, to prevent harmful side effects and to increase drug bioavailability. For over 20 years, the potential benefit of nanotechnology is appreciated by most of the researchers and it is providing vast improvements in drug delivery and drug targeting. New advancements in the drug delivery strategies are minimizing the unwanted toxicities and improving the efficacy of the treatments.
Pulmonary delivery of drug has become an attractive target and of tremendous scientific and biomedical interest in the health care research area as the lung is capable of absorbing pharmaceuticals either for local deposition or for systemic delivery. The respiratory epithelial cells have a prominent role in the regulation of airway tone and the production of airway lining fluid. In this respect, growing attention has been given to the potential of a pulmonary route as a non-invasive administration for systemic and local delivery of therapeutic agents, because the high permeability and large absorptive surface area of lungs, (approximately 70-140 m2 in adult humans having extremely thin absorptive mucosal membrane) and good blood supply. The alveolar epithelium of the distal lung has been shown to be an absorption site for most of the therapeutics and various macromolecules. Further advantages over peroral applications are the comparatively low enzymatic activity, rapid absorption of drug and the capacity for overcoming first-pass metabolism. It has been already reported that, the local respiratory disorders and some systemic diseases can be well treated by delivering the drugs through pulmonary route. This includes the topical treatment of asthma, local infectious diseases, pulmonary hypertension, the systemic use of insulin, human growth hormones, and oxytocin Presently this is true for many biotherapeutics currently injected intravenously, such as growth hormones, glucagons, or insulin, each of which could possibly be delivered to humans by inhalation were the efficiency of inhalation therapy is greater.
Understanding the transport and deposition of inhaled aerosols is of fundamental importance to inhalation therapy. Herein we address issues that related to the technical, physiological, and efficacy aspects of pulmonary drug delivery system. This review also focused on transepithelial transport and mechanisms of pulmonary administration. In addition, polymer selections in dosage and types of delivery devices have also been compiled.
IDEAL CHARACTERSTICS OF THERAPEUTIC AEROSOL
1. Contain a safe and efficacious drug.
2. Contain minimal quantities of inert excipients.
3. Monodisperse, small particle size
4. Low velocity after generation
5. High concentration and rate of generation
6. Highly reproducible characteristics
7. Low bioburden (solids) or sterile (liquids)
ADVANTAGES OF PULMONARY DRUG DELIVERY
1. Inhaled drug delivery puts drug where it is needed.
2. It requires low and fraction of oral dose i.e. drug content of one 4 mg tablet of salbutamol equals to 40 doses of meter doses.
3. Pulmonary drug delivery having very negligible side effects since rest of body is not exposed to drug.
4. Onset of action is very quick with pulmonary drug delivery.
5. Degradation of drug by liver is avoided in pulmonary drug delivery.
6. In asthma and diabetes requires long term treatment if it is given by pulmonary drug delivery safety is maximum because rest of body is not exposed to drug.3
CHALLENGES IN PULMONARY DRUG DELIVERY
Low Efficiency of inhalation system
Efficiency of presently available inhalation systems has generally too low which is important challenge in pulmonary drug delivery. Optimum aerosol particle size is very important for deep lung delivery. Optimum particle size for deep lung deposition is 1-5 mm. Aerosol system should have to produce optimum size particles because they are too small, they will be exhaled. If the particles are too large, they affects on the oropharynx and larynx.
Less drug mass per puff
To get adequate effect with the pulmonary drug delivery practical delivery of many drug which require milligram doses but With most existing systems, the total amount of drug per puff delivered to the lower respiratory tract is too low less than 1000 mcg .
Poor formulation stability for drug
Most traditional small molecule asthma drugs are crystalline and, in the case of corticosteroids, relatively moisture resistant in the dry state. They are also rather stable in liquids as compared to most macromolecules, which are unstable in the liquid state, amorphous, and highly moisture sensitive in the dry state.
Improper dosing reproducibility
Following are reason for Poor dosing reproducibility like worsening of diseases’, problem in device, unstabality of formulation. To get maximum dose reproducibility patient education play important role.
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STRUCTURE AND FUNCTION OF THE LUNG
Airways
The human respiratory system can be divided in two functional regions: the conducting airways and the respiratory region. The conducting airways, which are composed of the nasal cavity and associated sinuses, the pharynx, larynx, trachea, bronchi, and bronchioles, filter and condition the inspired air.
Blood circulation
Two different circulatory systems, the bronchial and the pulmonary, supply the lungs with blood. The bronchial circulation is a part of the systemic circulation and is under high pressure. It receives about 1% of the cardiac output and supplies the airways (from the trachea to the terminal bronchioles), pulmonary blood vessels and lymph nodes with oxygenated blood and nutrients and conditions the inspired air.
Major components of the lung – barriers to drug absorption
Epithelium
The airway epithelial cells provides a tight ciliated barrier that clears the airways from debris trapped in the airway mucus, prevents indiscriminant leakage of water and solutes into the airways, secretes components for the airway lining fluid and mucus layer, repairs injuries to the epithelium, and modulates the response of inflammatory cells, vessels, and smooth muscle.
Endothelium
The lung is unique among tissues in that about 40% of its total cellular composition is capillary endothelium, which is the largest capillary endothelial surface in the body.
Alveolar macrophages
The alveolar macrophages are found on the alveolar surface. These phagocytic cells play important roles in the defense mechanisms against inhaled bacteria and particles that have reached the alveoli.
Interstitium and basement membrane
The interstitium of the lung, the extracellular and extravascular space between cells in the tissue, contains a variety of cells (fibroblasts, myofibroblasts, pericytes, monocytes, lymphocytes, plasma cells), collagen, elastic fibers, and interstitial fluid.
Lymphatic system
The pulmonary lymphatic system contributes to the clearance of fluid and protein which has filtered from the vascular compartment into the lung tissue interstitium and helps to prevent fluid accumulation in the lungs.
Epithelial lining fluid
Solid drugs particles delivered to the respiratory tract need to be wetted and dissolved before they can exert their therapeutic activity. Although the humidity in the lung is near 100%, the volume of the epithelial lining fluid is small.
Surfactant
The lung surfactant is synthesized and secreted by the alveolar type II cells and comprises a unique mixture of phospholipids and surfactant-specific proteins.
Mucociliary clearance
The mucociliary clearance is probably the most important mechanical host defense in the lung. By the coordinated movements of cilia, the mucus is swept out of the nasal cavity and lungs, respectively, towards the pharynx where it is swallowed. In the nose, clearance rates of 3-25 mm/min have been shown in normal subjects.
Schematic illustration of a lateral view of epithelial cells in the different regions of the human lung with the relative cell size and the surface fluid thickness
TRANSEPITHELIAL TRANSPORT OF DRUGS
The development of drug delivery systems for pulmonary application requires a detailed knowledge of the lung in its healthy, as well as various diseased states. The lung is composed of more than 40 different cells. The human respiratory system is a complex organ system having a close structure-function relationships. This system mainly comprise of two vital regions: the conducting airways and the respiratory region. The airway is further divided into nasal cavity, and associated sinuses, and the nasopharynx, oropharynx, larynx, trachea, bronchi, and bronchioles. The respiratory region consists of respiratory bronchioles, alveolar ducts, and alveolar sacs. The transepithelial transport of drugs along the respiratory epithelium from these two regions is characterized by large quantitative differences. The drug transport in upper airways is limited due to smaller surface area and lower regional blood flow. Furthermore, this region possesses a high filtering capacity and removes up to 90% of delivered drug particles. Further inhaled substances deposit on the mucus layer, which coats the walls of the conducting airways. Mucus is secreted by goblet and submucosal gland cells and forms a gel-like film consisting of mucin as the major component. Ciliated cells are also present in this region they cause propulsion of mucus upward and out of the lung, thus the lung will be cleared of foreign substances. In contrast, the smaller airway and alveolar space accounts for more than 95% of the lung's surface area and is directly connected to the systemic circulation via the pulmonary circulation. Apart from this, morphology of the major alveolar epithelial cells, the pulmonary blood-gas barrier system, and size of pores and tight junction depth of alveolar and endothelial cells are most likely reasons that govern the transepithelial drug transport.
BIOLOGICAL MODELS FOR ASSESSMENT OF PULMONARY DRUG ABSORPTION
In vivo animal models
In vivo pharmacokinetic experiments in animals provide data on the fate of a drug and its metabolites in the body by assessment of the drug concentration in plasma or tissues. In the absence of a significant amount of human absorption data, accurate in vivo pharmacokinetic investigations in animals are important to establish in vitro-in vivo relationships. For determination of the pulmonary absorption rate and bioavailability, plasma is sampled at predetermined time points after pulmonary drug administration and analyzed for drug content.
There are several models for this:
1. Passive inhalation.
2. Head only or nose only inhalation systems
3. Direct intratracheal administration
4. Intranasal administration
Isolated and perfused lungs or Ex vivo models
By the use of isolated and perfused lung models, lung-specific pharmacokinetic events can be investigated without the contribution of systemic distribution, metabolism, and elimination. In these models, the structural and cellular integrity of the lung tissue, the permeability barriers, interaction between different cell types, and biochemical activity are maintained.
Cell culture models
The inaccessibility and heterogeneous composition of the airway epithelium makes it difficult to mechanistically evaluate pulmonary cellular integrity and physiological functions. For investigations of drug transport mechanisms, precise dosing and sampling, as well as defined local drug concentration and surface area of exposure, are important parameters that need to be controllable and reproducible. Therefore, a variety of airway and alveolar epithelial cell culture models of animal and human origin have been established as in vitro absorption models.
Cell culture models are of three types:
a) Continuous cell cultures.
b) Primary cell cultures.
c) Air interface cultures.
MECHANISMS AND WAYS OF PULMONARY DRUG ADMINISTRATION
Through pulmonary route, the drug can be administered by two primary modes: first, intranasal administration, which has anatomical limitation, such as narrower airway lumen, second, oral inhalative administration.
By oral inhalative administration far better results can be expected as it allows to administer very small particles with a concentration loss of only 20% in comparison with 85% by nasal route. Oral inhalative administration can again be classified as intratracheal instillation and intratracheal inhalation. The most common method used in laboratory is the intratracheal instillation. In the intratracheal instillation, a small amount of drug solution or dispersion is delivered into the lungs by a special syringe. This provides a fast and quantifiable method of drug delivery to the lungs. The localized drug deposition is achieved with a comparatively small absorptive area. So, the instillation process is much simple, non-expensive, and has non-uniform drug distribution. In preclinical animal studies, intratracheal instillation has frequently been used to assess the pulmonary absorption and systemic bioavailability, especially with regard to the precise dosing and effectiveness associated with this method. However, intratracheal instillation is not a physiological route for application, and results obtained from these studies may not be transferable to aerosol applications in humans.
On the contrary, inhalation method uses aerosol technique by which we can get more uniform distribution with great penetration. However, this method is more costly and difficult to measure the exact dose in lungs. The deposition of drug by aerosol administration in the pulmonary airway mainly takes place by three mechanisms:-gravitational sedimentation, inertial impaction, and diffusion. If the drug particle size is comparatively bigger, then, deposition takes place by first two mechanisms where, either sedimentation occurs due to gravitational force or inertial impaction occurs due to hyperventilation. When the particle size is smaller they deposit mainly by diffusion mechanism, which in turn is based on the Brownian motion. Apart from the pulmonary morphological aspects and ventilatory parameters size of the particles or droplets and the geometry is quite important. The size of particle or droplet in terms of diameter along with the surface electrical charges, shape of the particulate matter if it is a fiber and hygroscopy also having profound influence on drug deposition through pulmonary route. The term mass median aerodynamic diameter is used and it depends on size, shape, and density of the particulate system.
In fact, the three principal mechanisms of particle deposition in the respiratory tract rely on the size of the inhaled particles.
- Impactionis the inertial deposition of a particle onto an airway surface. It occurs principally at or near airway bifurcations, most commonly in extrathoracic and large conducting airways, where flow velocities are high and where rapid changes in the direction of bulk airflow often take place, generating considerable inertial forces. The probability of impaction increases with increasing air velocity, rate of breathing, particle size (>5µm) and density.
- Gravitational sedimentationis an important mechanism for deposition of particles over 0.5µm and below 5µm in size in the small conducting airways where the air velocity is low.
- Deposition due to gravityincreases with enlarging particle size and longer residence times but decreases as the breathing rate increases. Submicron-sized particles (especially those less than 0.5µm) acquire a random motion caused by the impact of surrounding air molecules. This Brownian motion may then result in particle deposition by diffusion, especially in small airways and alveoli, where bulk airflow is very low.
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CURRENT TECHNOLOGIES IN PULMONARY DRUG DELIVERY DEVICES
Following types of inhalation devices are present
· Inhalation drug delivery system by- metered dose inhalers
· Inhalation drug delivery system by —dry powder inhalers
· Inhalation drug delivery system by -nebulizer
A ) Inhalation drug delivery system bymetered dose inhalers
A metered-dose inhaler (MDI) is a complex system designed to provide a fine mist of medicament, generally with an aerodynamic particle size of less than 5 microns, for inhalation directly to the airways for the treatment of respiratory diseases such as asthma and COPD.
Advances in MDI Technology and Use Enantiomer Preparations of Inhaled Drugs
There has been much interest in the differences in effects of Enantiomer of many medications, and beta agonist adrenergic bronchodilators have received much attention. Recently levo salbutamol active enantiomer of salbutamol is present in market which is free from termers and palpitation that seen in salbutamol. Similarly that the (R)enantiomer of albuterol is mainly responsible for bronchodilator while the (S)enantiomer may stimulate airway reactivity. Data suggest, however, that after aerosol delivery, the systemic absorption for (R)albuterol is faster than for (S)albuterol and that, conversely, the lung retention of (S)albuterol is longer, which may be detrimental.
Generic proliferation of devices and medications
Nowadays new MDI and nebulizer brands are introduced regularly in pharma market. Even for those who watch this field, it is not unusual to hear a new, unfamiliar brand name regularly. One trend has been the move to generic MDIs and to over the counter availability. These are introduced in the literature by comparing them with well-known older devices. Often, documentation that generic brands or new devices are comparable to older ones is difficult to come by, so comparisons showing pharmacokinetic equivalency are useful.
New technologies to improve patient’s inhalation coordination with MDI
Spacers are used to improve patient coordination with MDI. Both adults and children often have difficulty coordinating the inhalation effort with the timing of the aerosol puff. Evidence indicates considerable intra and intersubject variability for the inhalation technique.
Flow gate valve technology in spacers
Certain company s spacer present in market which is static free with valve mechanism which increases drug dose reaching to lungs. Valves opens during inhalation and closed during exhalation this ensures that the residual dose is retained in spacer for subsequent inhalation.
The autohaler modified form of pMDI
The Autohaler TM is the first breath actuated or activated pressurized metered dose inhaler . Autoihaler solve the key problem of the pressurized metered dose inhaler (pMDI) viz. coordination of actuation with inhalation and does not rely on the patient's inspiratory effort to aerosolize the dose of medication unlike dry powder inhalers .Autohaler is modified form of pressurized metered dose inhaler.
B) Inhalation drug delivery device by dry powder inhalers
Today there are essentially two types of DPIs, those that use drug filled into discrete individual doses, e.g., either a gelatin capsule or a foil–foil blister, and those that use a reservoir of drug that meters out doses when required. Both are now widely available around the globe and are gaining broad acceptance. 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 the device and the powder is inhaled. The capsule residue must be discarded after use and a new capsule inserted for the next dose Multidose Devices -Multidose device uses a circular disk that contains either four or eight powder doses on a single disk. This typically would be treatment for one to two days. The doses are maintained in separate aluminum blister reservoirs until just before inspiration. This device is a true multidose device, having 60 doses in a foil–foil aluminum strip that is opened only at the point just prior to patient inspiration.
New developments in dry powder inhalation technology
Changes in the performance of the DPI can be achieved either through changes in the design of the device through changes in the powder formulation, or . described extensively, the forces governing the particle–particle interactions in the agglomerates and the forces playing a role in the deagglomeration process .Recent developments regarding the powder formulation aim at a reduction of the adhesive and cohesive forces between the particles to increase the FPF.
Supercritical fluid technology is applied to improve the surface properties of the drug substance Large porous particles have reduced inter-particulate forces because of their low density, the
irregular surface structure and/or reduced surface free energy . Moreover, these particles are claimed to have improved aerodynamic behavior in the airways, whereas phagocytosis of the
deposited particles in the alveoli is reduced . In another approach, smaller porous particles (3–5 mm) have been used to improve deagglomeration and lung deposition.
Changes in device technologies are few new developments really aim at an increase of the deagglomeration forces generated during the inhalation. It is well known that if the more efficient the force is, higher the FPF will be. A main classification parameters in the new
device developments is whether or not the powder deagglomeration is power assisted (active devices) or depends on the kinetic energy of the inhalation flow generated by the patient (passive devices). Regarding the passive devices, recently two DPI devices were introduced that apply impaction forces for the generation of the aerosol. 12
Airclassifier technology in devices
This is another most important technology used in recent devices for pulmonary drug delivery. The inhaler contains a classifier (cyclone) chamber in which high inertial forces are applied onto the rotating particles. Moreover, the action of these forces on the larger agglomerates is sustained because they remain in the classifier for a certain period of time, which can be controlled by the classifier design and by the choice of carrier-size fraction. Air-classifier technology system one contains a cyclone chamber for particle deagglomeration. Modified form of Airclssifier technology is multiple air-classifier technology.
Multiple airclassifier technology
In this technology multiple classifier chambers are placed in a parallel arrangement, which further increases the dose that can be aerosolized. Another interesting point in this development is that the authors managed to develop a disposable DPI. The concept of a disposable inhaler is interesting because it reduces the chance of microbial contamination.
C) Inhalation drug delivery devices by nebulizer
Mainly there are two general types of nebulizer systems, the ultrasonic and the air jet. In ultrasonic nebulizers, ultrasound waves are formed in an ultrasonic nebulizer chamber by a ceramic piezoelectric crystal that vibrates when electrically excited. These set up high energy waves in the solution, within the device chamber, of a precise frequency that generates an aerosol cloud at the solution surface. The aerosol produced by an air jet nebulizer is generated
when compressed air is forced through an orifice, an area of low pressure is formed where the air jet exists. A liquid may be withdrawn from a perpendicular nozzle (the Bernoulli Effect) to mix
with the air jet to form droplets. A baffle (or baffles) within the nebulizer is often used to facilitate the formation of the aerosol cloud. Carrier air can be used to generate the “air jet.” alternatively, compressors may be used to generate the air stream. Nebulizers used today for drug delivery to the respiratory tract and are particularly useful for the treatment of hospitalized or nonambulatory patients.
LUNG COMPATIBILITY OF FORMULATION EXCIPIENTS/POLYMERS
The important attention to be given in the development of pulmonary drug delivery system is the compatibility of polymers used in the design of particulate carriers. The safety of these polymers must be first determined and their compatibility with lung fluid is of great concern. The polymers used to prolong the release rate for chronic use may accumulate in the lung, especially in the lung periphery, which is not served by mucociliary clearance. Chronic inhalation of carrier particles has been shown to induce depletion of surfactant with subsequent recruitment of phagocytic cells. The chances of presence of residual solvent in the final product leads to pulmonary toxicity. Therefore, processing techniques and formulation components must be thoroughly screened in order to avoid the toxic consequences. Carriers used in the design of dry powder inhalation formulations, such as sugars, and cyclodextrins can cause bronchoconstriction in many of the hypersensitive individuals. Chronic use of proteins and other carriers, such as absorption enhancers and enzyme inhibitors, can produce immunogenicity, local irritation, and toxicity. Increased permeability may also allow transport of other toxins and antigens across the epithelial barrier. These are some vital issues, which can be properly rectified through suitable models.
TECHNIQUES OF MAKING PARTICULATE MATTER FOR LUNG DELIVERY
Many conventional techniques have been reported to produce DPI formulations. However, these methods have number of limitations, such as particle size, size distribution, shape and poor control over powder crystallinity. These problems can be rectified by specialized milling techniques. Jet-milling of drug under nitrogen gas with new nanojet milling instrument is the most suitable method for creating nanoparticles meant for pulmonary drug delivery. Here, some of the important techniques are discussed in brief.
Spray drying technique
Spray drying is an advanced pharmaceutical manufacturing process used to efficiently produce respirable colloidal particles in the solid state. Spray drying was explored in the 1980s as an alternative means of producing fine particles for pulmonary delivery. In this process, the feed solution is supplied at room temperature and pumped to the nozzle where it is atomized by the nozzle gas. The atomized solution is then dried by preheated drying gas in a special chamber to remove water moisture from the system, thus forming dry particles. This method is more promising in producing the particles of above 2-μm size. This method is reported to have better control on particle formation and hence can be easily translated to large scale production. This process is also suitable for thermolabile materials, such as proteins and peptides, because mechanical high- energy input is avoided in this process. More importantly, spray-drying can result in uniform particle morphology.
Spray freeze drying method
This method was explored for pharmaceutical application in early 1990s. It is an advanced particle engineering method, which combines spray-drying and freeze-drying processing steps. It involves spraying the drug solution into liquid nitrogen as a freezing medium followed by lyophilization. This method produces light and porous particles and high fine particle fraction with improved aerosol performance and almost 100% yield at subambient temperatures. Thermolabile protein and peptide substances, such as insulin and plasmid DNA, can also be formulated into dry powder inhalation products. However, this is an expensive process restricted for only expensive drug.
Supercritical fluid technology
The basic feature of this process is the controlled crystallization of drugs from dispersion in supercritical fluids, carbon dioxide. This method has been used in the pharmaceutical field for production of microparticles, nanoparticles, liposomes, and inclusion complexes. This method is used for the production of particulate pulmonary drug delivery systems containing proteins and peptides, and also used to improve the formulation properties of certain drug candidates.
Solvent precipitation method
This method involves sono-crystallization and micro-precipitation by opposing liquid jets. Crystalline drug particles with narrow size distribution could be prepared by direct controlled crystallization. Inhalable particles can be produced by rapid precipitation from aqueous solutions using antisolvents. Recently, ultrasonic radiation has been applied to control the precipitation. Various antiasthmatic drugs were prepared using the sono-crystallization technique.
Double emulsion/solvent evaporation technique
This method involves preparation of oil/water emulsion with subsequent removal of the oil phase through evaporation. The organic solvent diffuses out of the polymer phase and into the aqueous phase, and is then evaporated, forming drug- loaded polymeric nanoparticles. By this method, biodegradable polymers have been intensively investigated as carriers for respiratory solid drug nanoparticles.
Particle replication in nonwetting templates
Particle replication in non wetting templates (PRINT) is top-down particle fabrication technique developed by Dr. Joseph DeSimone and his group. This technique is able to produce uniform-sized organic micro- and nanoparticles with complete control of size, shape, and surface functionality, and helps in loading of small organic therapeutics, proteins, peptides, oligonucleotides, siRNA contrast agents, radiotracers, and flurophores.
CHARACTERIZATION OF PARTICULATE MATTER
Nanoparticle characterization is necessary to establish understanding and control of nanoparticle synthesis and applications. The primary characterization of NPs is the size of the newly formed particles.
Particles with a very small size (<1000nm), low charge, and a hydrophilic surface are not recognised by the mononuclear phagocytic system(MPS) and, therefore, have a long half life in the blood circulation which is essential for targeting NPs to target brain.
Characterization is done by using a variety of different techniques, mainly drawn from materials science.
Common techniques are:
* Electron microscopy [TEM,SEM]
* Atomic force microscopy [AFM]
* Dynamic light scattering [DLS]
* Differential scanning colorimetry [DSC]
* X-ray photoelectron spectroscopy [XPS]
* Powder x-ray diffractometry [XRD]
* Fourier transform infrared spectroscopy [FTIR]
* Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry [MALDI-TOF]
* Coulter current method
* Microelectrophoresis
* Zeta potential
* Cascade Impaction
* Ultraviolet-visible spectroscopy
* Dual polarisation interferometry and
* Nuclear magnetic resonance [NMR]
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RECENT ADVANCES IN FORMULATION OF PULMONARY DRUG DELIVERY
Effective inhalable medication are produced by drug formulation. Formulation stability is another challenge in producing pulmonary drug delivery. Formulation is responsible for keeping drug pharmacologically active, it must be efficiently delivered into the lungs, to the appropriate site of action and remain in the lungs until the desired pharmacological effect occurs. Depending upon disease condition effective formulation release drug, such as insulin for diabetes, must be deposited in the lung periphery to ensure maximum systemic bioavailability. Thus, a formulation that is retained in the lungs for the desired length of time and avoids the clearance mechanisms of the lung may be necessary. Research into dry powder formulations has been an area of growth in recent years and will be the focus of this section. Various techniques are used to made advances in dry powders formulation for inhalation involves either ,micronization via jet milling, precipitation, or spray drying using various excipients, such as lipids and polymers, or carrier systems like lactose.
Lactose carrier systems
Recent advances in inhalation therapy have sparked considerable biomedical interest in the development of novel particle technologies for respiratory drug formulation .The cohesive
powders with poor flow arises if the surface electric forces associated with the particles exceed the gravitational force acting upon them’. To overcome this problem, the drug is blended with a
coarse carrier system (30–100 μm), such as lactose. At present, marketed dry powder inhalers contain either the drug alone or mixed with a bulk carrier, usually lactose (α-lactose monohydrate). Lactose has an established safety profile and improves the flow properties of the formulation necessary for reproducible filling and promoting dosing accuracy.
Liposomes
Liposomes, as a pulmonary drug delivery vehicle, have been studied for years and used as a means of delivering phospholipids to the alveolar surface for treatment of neonatal respiratory distress syndrome. More recently, they have been investigated as a vehicle for sustained-release therapy in the treatment of lung disease, gene therapy and as a method of delivering therapeutic agents to the alveolar surface for the treatment of systemic diseases. Sustained release from a therapeutic aerosol can prolong the residence of an administered drug in the airways or alveolar region, minimize the risk of adverse effects by decreasing its systemic absorption rate, and increase patient compliance by reducing dosing frequency. A sustained-release formulation must avoid the clearance mechanisms of the lung, the mucociliary escalator of the conducting airways and macrophages in the alveolar region.
Large porous particles
Pulmospheres are the new type of aerosol formulation is the large porous hollow particles,. They have low particle densities, excellent dispersibility and can be used in both MDI and DPI delivery systems. These particles can be prepared using polymeric or nonpolymeric excipients, by solvent evaporation and spray-drying techniques. Pulmospheres are made of phosphatidylcholine, the primary component of human lung surfactant. The large size of Pulmospheres allows them to remain in the alveolar region longer than their nonporous counterparts by avoiding phagocytic clearance. After intratracheal administration into rats, only 8% and 12.5% of macrophages contain Pulmospheres particles immediately and 48 h after inhalation, respectively, compared with 30% and 39% of macrophages containing nonporous particles during a similar time interval.
Biodegradable polymers
Apart from Liposomes, biodegradable polymer microspheres are currently being studied as sustained release pulmonary drug carriers. Polymers such as polylacticacid used in medical applications such as sutures orthopedic implants and medical dressings, and poly glycolic acid have been investigated. Although a limited amount of research has been published in this area, the sustained-release profiles achieved with corticosteroids appear promising. However, the toxicity of this type of formulation has not yet been established for lung delivery.
ADVANCES IN PROPELLANTS USED IN PULMONARY DRUG DELIVERY DEVICES
Recently HFA propellants are a new alternative for CFC propellants in pulmonary drug delivery devices. Generally the higher vapor pressures of the HFAs (particularly 134a) have the potential to generate aerosols of higher quality than the “old” CFC formulations. However, except in a few notable instances, potential product improvements have been sacrificed for development costs and time as per market need.
RECENT TREND IN APPLICATIONS OF PULMONARY DRUG DELIVERY
New applications of pulmonary drug delivery
Apart from asthma and COPD recentaly pulmonary drug delivery is used for following indication
* Insulin by Aerosol
* Treatment of Migraine
* Nicotine Aerosol for Smoking Cessation
* Aerosols for Angina.
* Aerosol Vaccination.
* Alpha 1 Antitrypsin
* Aerosols in Transplantation
* Pulmonary arterial hypertension
* Acute Lung Injury
* Surfactant Aerosol
* Gene Therapy via Aerosol
* In Cancer chemotherapy
* Pentamidine Aerosol
* Gentamycin aerosol
* Ribavirin Aerosol
* Zanimivir with revolizer for swine flue.
* Aerosols used in clinical investigations of disease
* Inhaled Drug Delivery for Tuberculosis Therapy
* Pulmonary delivery of lower molecular weight Heparin.
* Controlled delivery of drugs to lungs
* Pulmonary delivery of drugs for bone disorders
* Pulmonary delivery of opioids as pain therapeutics
CONCLUSION
There have been a number of significant achievements in technologies to express and deliver drugs by pulmonary route. Improvements in the aerosol’s velocity, particle size, or moment of release have been achieved. But drug administration via pulmonary route is a difficult and complex process, comprising not only aspects from technology but also from physiology, clinical application or patient use.. This shows that for different diseases or even for each individual drug, the required conditions for optimal administration differ substantially and that a perfect inhaler (plat-form) suitable for all types of drugs and diseases is a fiction.
Advantages of DPIs such simple and cheap devices, their robustness, portability, easy of use as but systems that can disperse larger amounts of powder (upto 50 mg) within one breath is Major challenges that remain for dry powder inhalation. To maintain stability of powder formulation is another challenge associated with DPI.
As compare to classic nebulizers or MDIs the new liquid inhalation systems are certainly better option but many liquid aerosol generation systems require an external energy source and contain complex electronics. Due to this there is increase failure risk and reduce the freedom of the patient. Further relevant aspects are the dependency of the device’s performance on the physicochemical characteristics of the liquid formulation. Advancements in pulmonary drug delivery should not only focus on only one technological aspect, but also need to focus on other aspects. And there is a wide scope for the researchers to investigate and demonstrate good agreement between in-vitro, ex-vivo, and in-vivo tests used to predict drug absorption from the intact animal and, which may therefore present a solid basis for future advancement in nanomedicine strategies for pulmonary drug delivery.
BIBLIOGRAPHY
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