INTRODUCTION:

To optimize the delivery of drugs, in this field, particular considerations have been focused on the forms (geometric design) of the particles, their physical states (amorphous or crystalline state) and their sizes ranging from the nanometric to the micrometric scale¹. In this field it was also suggested to use the microencapsulation concept in order to increase the bioavailability of drug administration by pulmonary route. Face to these technological progresses, recently, macromolecular advances have been also done in order to administer drugs via targeting dosage forms by pulmonary rout for systemic applications. The conception of this new drug delivery system (DDS) is to better control drug pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity and biorecognition of systems in the quest for improved efficacy². The pulmonary rout of administration has been used for many years for the local treatment of lung diseases. More recently, systemic drug absorption has been investigated, e.g., for the treatment of diabetes mellitus and pain relief³. Porous powder is an attractive modality for the treatment of many pulmonary infection, pulmonary hypertension and lung cancers. For these diseases, macromolecular targeted medication delivery to the lung is highly desirable because it results in effective drug concentration at site of pathology with minimal systemic absorption and side effects.

This approach is likely to achieve therapeutic effects with smaller drug doses as compared to the parenteral route. For most indication, an ideal inhaled therapeutic should provide sustained effects with a minimal number of administrations⁴.The future of pulmonary drug delivery, whether for macromolecules or small molecules, appears to be broadening. Delivery of macromolecules to the lung periphery offers many advantages over injection and other noninvasive method. As the fields of biotechnology, genome research, and protein therapeutics continue to burgeon, the opportunities for aerosol delivery of these compounds expand accordingly. The Macromolecular drugs which tried through pulmonary drug delivery are described in Table 1.

1. Problems in drug delivery of macromolecules:

Because of their size and delicacy, peptides, proteins, and other macromolecules have traditionally been systemically administered via injection. But there are problems with a administering them this way, most patients do not like the pain and inconvenience of injection, particularly when required repeatedly for the treatment of chronic disease such as diabetes or multiple sclerosis. This dislike can result in poor patient compliance and inadequate disease management with the development of more long-term and frequently administered injection drugs (e.g. growth factors, anti-infective, and other chronic disease treatments) the pharmaceutical industry has increasingly sought noninvasive alternatives to needle injection.

Table 1: Macromolecular drugs tried through pulmonary drug delivery

Growth harmone

Alpha-1 proteinase inhibitor

Parathyroid harmone

Somatostatin

Erythropoietins

Follicle stimulating harmone

Nerve growth factor

Adenosine deaminase

Gene vectors

Chorionic gonadotropin

Tissue plasminogen activator

Urokinase

Human deosyribonuclease

Calcitonin

Nesiritide

Colony-stimulating factor

Interferons

Interleukins and antagonists

Luteinizing hormone releasing hormone

Vaccines

Monoclonal antibodies

Heparins

Coagulation factor

Granulocyte colony stimulating factor

Streptokinase

Traditional noninvasive delivery very systems have not proved effective for macromolecules. Pills, tablets and oral solution are unsuitable because of poor absorption or inactivation by gastric juices and digestive enzymes. Transdermal delivery systems are also inadequate because of the size constraints of macromolecules or other inherent physical properties that prevent them from crossing skin layers without the addition of irritating enhancers. Research has also shown that the nasal route has low natural bioavailability and high variability for proteins and peptides^4,5. The natural bioavailability of macromolecules when delivered nasally is generally, 2%. To achieve higher system efficiency and greater bioavailability, penetration enhancers are required that can cause local irritation and long- term mucosal injury.

2. Mechanism of Respiratory Deposition:

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 as:-

Depending on the particle size, air flow, and location in the respiratory system, particle deposition occurs via on of the following principal mechanisms:-

2.1 Impaction:

Each time the air flow changes due to a bifurcation in the airways, the suspended particles tend to travel along their original path due to inertia and may impact on an airway surface. This mechanism is highly dependent on aerodynamic diameter, since the stopping distance for very small particles is quite low. Impaction occurs mostly in the case of larger particles that are very close to airway walls, near the first airway bifurcations. Therefore, deposition by impaction is greatest in the bronchial region. Impaction accounts for the majority of particle deposition on a mass basis.

2.2 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. The rate of sedimentation is dependent on the terminal settling velocity of the particles, so sedimentation plays a greater role in the deposition of particles with larger aerodynamic diameters. Hygroscopic particles may grow in size as they pass through the warm, humid air passages, thus increasing the probability of deposition by sedimentation.

2.3 Interception:

Interception occurs when a particle contacts an airway surface due to its physical size or shape. Unlike impaction, particles that are deposited by interception do not deviate from their air streamlines. Interception is most likely to occur in small airways or when the air streamline is close to an airway wall. Interception is most significant for fibers, which easily contact airway surfaces do to their length. Furthermore, fibers have small aerodynamic diameters relative to their size, so they can often reach the smallest airways.

2.4 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. Diffusion is the net transport of particles from a region of high concentration to a region of lower concentration due to Brownian motion. Brownian motion is the random wiggling motion of a particle due to the constant bombardment of air molecules. Diffusional deposition occurs mostly when the particles have just entered the nasopharynx, and is also most likely to occur in the smaller airways of the pulmonary (alveolar) region, where air flow is low ^{4, 5}.

3. Porous microparticle:

Microparticles are small particles (1-1000µ) range used as drug carriers of drugs and other therapeutic agents. These are monolithic spherical structures with the drug distributed throughout the microsphere matrix either as a molecular dispersion or as particle dispersion^{6, 7}.

A major advantage of large porous particles lies in the fact that they disperse for more easily than standard nonporous particles of similar aerodynamic diameter, thus they can be effectively dispersed even from relatively simple inhaler systems^8,9,10.This nontraditional mode of pulmonary drug delivery is actually more efficient than the traditional method, porous particle possess densities sufficiently small to create aerodynamic particle sizes in the range of 1-5 μm, and for deep- lung delivery 1-3 μm. The large size and low mass density due to porous structure helped their deep lung deposition thus avoiding phagocytic clearance^{11, 12, 13}.

However, unfortunately the protein release behavior of these porous particles was unsatisfactory despite deferent type of polymer for the sustained release. The release of recombinant human growth hormone (rh GH) from the porous poly (lactide-co-glycolide) (PLGA) microparticle release up to 100wt. % in only one day^13,14. These porous particles were characterized by initial bursts and short-term release in respiratory tract. Porous microparticles are attractive modality for the treatment of many pulmonary disorders is shown in table 2 and medical conditions that could benefit from pulmonary delivery of porous microparticle are shown in table 3.

Table 2: Most common problems of the respiratory system

S no.

Pulmonary disorder

Reference

Asthma

Bronchiolitis

Chronic obstructive pulmonary disease(COPD)

Common cold

Cough

Cystic fibrosis

Lung cancer

Pneumonia

Pulmonary hypertension

Respiratory diseases of newborns

Table 3: Medical conditions that could benefit from pulmonary delivery of porous microparticle

S no.

Symptoms

Reference

Pain

Panic and anxiety

Anaphylaxis

Cardiac arrhythmias

Other cardiovascular conditions

Diarrhea

Spasms

Insomnia

Nausea and vomiting

Nicotine withdrawal

Urinary incontinence

4. Effervescent Technology:

Effervescent powders have not previously been used for the pulmonary route of administration; effervescent reaction adds an active release mechanism to the pulmonary rout of administration^15,16. Effervescence is the reaction (in water) of acids and bases producing carbon dioxide. The chemical reaction that creates the fizz in effervescent bath and shower products is quite simple. An acid is used to neutralize a carbonate salt. This releases carbon dioxide gas, the salt of the acid, and water. Obviously, the carbon dioxide gas is the fizzing that characterizes effervescent products.

The Effervescent Reaction:

Acid + Carbonate Salt _ CO2_ + Acid Salt + H20

Ex: Citric Acid + 3NaHCO3 _ 3CO2_ + Na3Citrate + 3H20

There are a few points here that are not so obvious, but are very important. First, water is needed to start the reaction. Without water, neither the acid nor the carbonate can dissociate. If there is no dissociation, the effervescent reaction cannot start. Once the reaction starts, however, it generates more water. This means that effervescent products must be carefully formulated, produced in appropriate environments and packed properly. Otherwise their inherent instability can ruin them.

4.1 Raw Materials for Effervescent Products:

Since it is the source of the carbon dioxide, the carbonate salt is a key material in an effervescent formula. The most commonly used carbonate salts are shown in table 4.

Table 4: Commonly used carbonate salts in effervescent technology

Properties	Na₂Co₃	NaHCo₃
Molecular weight	106	84
Eq. of Acid to Neutralize	2	1
% Co₂	41.5	52.4

The other key component in an effervescent composition is the acid. It reacts with the carbonate salt, releasing the CO2 gas. Most commonly used acid in effervescent technology are shown in table 5.^16,17,
18

Table 5: Commonly used Acids in effervescent technology

Properties	citric	Fumaric	Adipic	Malic
Molecular weight	192.1	116.1	146.1	134.1
Moles of Acidity	3	2	2	2
Eq. weight	64.05	58.05	73.05	67.05
Solubility %	68.6	1.1	1.4	55.8

5. Mucoadhesive Microparticle:

Mucoadhesion can be defined as the ability of macromolecules to adhere to mucosal tissues such as the respiratory mucosa, pseudostratified ciliated columnar epithelium with goblet cell and a lamina proprea containing, in addition to connective tissue, numerous seromucous glands and in some regions many thin walled veins that line the airway¹⁹. Mucoadhesive drug delivery systems promise several advantages that arise from localization at a given target site, prolonged residence time at the site of absorption, and an intensified contact with the mucosa increasing the drug concentration gradient hence, uptake and consequently bioavailability of the drug may be increased and frequency of dosing reduced with the result that patient compliance is improved. Some of the common classes of mucoadhesive polymer.

Mucoadhesion can improve microparticle attachment to the respiratory mucous layer for the localization of the active agents to a particular site of action. Polymers have played important role in designing such systems so as to increase the residence time of the active agent at the desired location. Polymer used in mucosal delivery system may be natural or synthetic origin. Polymers used in mucoadhesive microparticle are shown in table 6^{20, 21}.

5.1 New Generation of Mucoadhesive Polymer:

They adhere to the mucus non-specifically, and suffer short retention times due to the turnover rate of the mucus. The chemical interactions between mucoadhesive polymers and the mucus or tissue surfaces are generally non-covalent in nature, and are classified as consisting mostly of hydrogen bonds, hydrophobic, and electrostatic interactions However, newer polymers are capable of forming covalent bonds with the mucus and the underlying cell layers, and hence, exhibit improved chemical interactions.

The new generation of mucoadhesive can adhere directly to the cell surface, rather than to mucus. They interact with the cell surface by means of specific receptors or covalent bonding instead of non-specific mechanisms, which are characteristic of the previous polymers. We have chosen to focus on recently discovered bioadhesive polymers in this review. Examples of such are the incorporation of l-cysteine into thiolated polymers and the target-specific, lecithin mediated adhesive polymers. These classes of polymers hold promise for the delivery of a wide variety of new drug molecules, particularly macromolecules, and create new possibilities for more specific drug– receptor interactions and improved targeted drug delivery.

5.2 Thiolated Mucoadhesive Polymers:

Through a covalent attachment between a cysteine (Cys) residue and a polymer of choice, such as polycarbophil, poly (acrylic acid), and chitosan a new generation of mucoadhesive polymers have been created^22,23,24. The modified polymers, which contain a carbodiimide-mediated thiol bond, exhibit much-improved bioadhesive properties. Investigations of the GI epithelial mucus have clarified the structure of this gel-like biopolymer²⁵. With more than 4500 amino acids, the enormous polypeptide backbone of mucin protein is divided into three major subunits; tandem repeat array, carboxyl and amino-terminal domains. The carboxyl-terminal domain contains more than 10% of cysteine residues. The amino-terminal domain also contains Cys-rich regions. The Cys-rich sub-domains are responsible for forming the large oligomers of mucin through disulfide bonds²⁶. Based on the disulfide exchange reaction, disulfide bonds between the mucin glycoprotein and the thiolated mucoadhesive polymer can potentially be formed, which results in a strong covalent interaction²⁷. Other improved mucoadhesive properties of the thiolated polymers, such as improved tensile strength, high cohesive properties, rapid swelling, and water uptake behavior, have made them an attractive new generation of bioadhesive polymers.

5.3 Mucoadhesive Polymers as Enzyme Inhibitors and Permeation Enhancers:

It has been shown that some mucoadhesive polymers can act as an enzyme inhibitor. The particular importance of this finding lies in delivering therapeutic compounds that are specifically prone to extensive enzymatic degradation, such as protein and polypeptide drugs. Investigations have demonstrated that polymers, such as poly (acrylic acid), operate through a competitive mechanism with proteolytic enzymes. This stems from their strong affinity to divalent cations (Ca2+, Zn2+)^{28, 29}. These cations are essential cofactors for the metalloproteinase, such as trypsin. Circular dichroism studies suggest that Ca²⁺ depletion, mediated by the presence of some mucoadhesive polymers, causes the secondary structure of trypsin to change, and initiates a further auto degradation of the enzyme^28,
29.

The increased intestinal permeability of various drugs in the presence of numerous mucoadhesive polymers has also been attributed to their ability to open up the tight junctions by absorbing the water from the epithelial cells. The result of water absorption by a dry and swellable polymer is dehydration of the cells and their subsequent shrinking. This potentially results in an expansion of the spaces between the cells (increased radius of the paracellular pathway)^30,
31.

5.4 Theories of Mucoadhesion:

There are six general theories of adhesion, which have been adapted for the investigation of mucoadhesion are described as below

5.4.1 Electronic Theory:

Electronic theory suggests that electron transfer occurs upon contact of adhering surfaces due to differences in their electronic structure. This is proposed to result in the formation of an electrical double layer at the interface, with subsequent adhesion due to attractive forces.

5.4.2 Wetting Theory:

Wetting theory is primarily applied to liquid systems and considers surface and interfacial energies. It involves the ability of a liquid to spread spontaneously onto a surface as a prerequisite for the development of adhesion. The affinity of a liquid for a surface can be found using techniques such as contact angle goniometry to measure the contact angle of the liquid on the surface, with the general rule being that the lower the contact angle, the greater the affinity of the liquid to the solid. The spreading coefficient (SAB) can be calculated from the surface energies of the solid and liquids using the equation:

S_AB = γ_B - γ_A- γ_AB

Where:-

γ_A is the surface tension (energy) of the liquid A.

γ_Ais the surface energy of the solid B.

γ_ABis the interfacial energy between the solid and liquid.

S_ABshould be positive for the liquid to spread spontaneously over the solid.

The work of adhesion (WA) represents the energy required to separate the two phases, and is given by:

W_A= γ_{A +}γ_B- γ_AB

The greater the individual surface energies of the solid and liquid relative to the interfacial energy, the greater the work of adhesion.

5.4.3 Diffusion Theory:

The diffusion theory describes inter diffusion of polymers chains across an adhesive interface. This process is driven by concentration gradients and is affected by the available molecular chain lengths and their mobility’s. The depth of interpenetration depends on the diffusion coefficient and the time of contact. Sufficient depth of penetration creates a semi-permanent adhesive bond.

5.4.4 Mechanical theory:

The mechanical theory assumes that adhesion arises from an interlocking of a liquid adhesive (on setting) into irregularities on a rough surface. However, rough surfaces also provide an increased surface area available for interaction along with an enhanced viscoelastic and plastic dissipation of energy during joint failure, which are thought to be more important in the adhesion process than a mechanical effect³².

5.4.5 Fracture theory:

The fracture theory differs a little from the other five in that it relates the adhesive strength to the forces required for the detachment of the two involved surfaces after adhesion. This assumes that the failure of the adhesive bond occurs at the interface. However, failure normally occurs at the weakest component, which is typically a cohesive failure within one of the adhering surfaces. Relative mucoadhesive performances of some potential mucoadhesive pharmaceutical polymer are shown in table 7.

6. Dry Powder Inhalers (DPI):

Dry powder inhalers utilize a capsule based dispersion chamber that consists of a simple cylinder through which permeates on inhalation. The chamber promotes dispersion of the large porous powders without impellers, motors, or other external energy sources. It is breath- activated and delivers porous powders from preloaded standard- size cellulose or plastic capsules. During use, a capsule is loaded into the chamber and punctured. When the patient’s breather, air enters the chamber tangentially, creating a strong internal vortex, this consistently empties the capsule. The turbulent airflow in the chamber ensures complete dispersion of the powder exiting the capsule. The spinning action of the capsule also creates a clear signal to verify delivery of the powder to the respiratory tract. Carrier particles are relatively dense, small and highly cohesive, and are therefore not easily dispersed. With porous powder, carrier powders are not needed, since the particles are inherently dispersible over a range of flow rates, these inhalers can delivery from small to large drug masses without any particular inhaler design change^33,3. Low inhaler cost is ensured by many of the characteristics of the inhaler, including the absence of carrier, the use of standard capsules, and the small number of inhaler parts. Dry powder inhalers are designed to eliminate the co-ordination associated with the Metered dose inhalers and other devices. There is a wide range of marketed pulmonary delivery device shown in figure 1 and dry powder inhalers devices are shown in table 8³⁴.

Table 8: Marketed devices of DPIs

S no.	Type	Device	Reference
1	Single-dose device	Aerolizer, Rotahaler	3,34
2	Multiunit dose devices	Diskhaler	3,34
3	Multiple unit doses sealed in blisters on a stripe moves through the inhaler	Diskhaler	34
4	Reservoir-type (bulk powder) system	Turbuhaler	34

7. Regulatory And Toxicity Issues:

Inhaled microparticles of different sizes can target into different regions of respiratory tract, including nasopharyngeal, tracheal, bronchial, and alveolar regions, with several mechanisms. Meanwhile, the surface chemistry, charge, shape and aggregation status of microparticles also have influences on their disposition efficacy³⁵. For example, inhaled large particles and deposit in the respiratory tract by distinctive mechanisms. Large particles deposit via inertial impaction, gravitation settling and interception mechanisms, while microparticles deposits via diffusion due to displacement when they collide with air molecules. The presence of albumin and phospholipids (e.g., lecithin) in alveolar epithelial lining fluid is important to facilitate epithelial cell uptake of microparticles after deposition in the alveolar space^36,37. Microparticles coated with them may translocate across the alveolo–capilliary barrier, whereas uncoated particles do not. Therefore, when evaluating the efficacy and fate of microparticles by inhalation delivery, all the variables should be taken into consideration. After delivery into the lung, some microparticles may be translocated to extrapulmonary sites and reach other target organs by cellular endocytosis, transcytosis, neuronal epithelial and circulatory translocation and distribution, which makes them desirable for medical therapeutic or diagnostic application^38,39,40. However, these features can also pose potential toxicity. Transcytosis absorbs microparticles and translocate them into the interstitial sites, where they gain access to the blood circulation via lymphatic’s resulting in distribution throughout the body. Neuronal translocation involves uptake of microparticles by sensory nerve endings embedded in airway epithelia, followed by axonal translocation to ganglionic and central nerve systems (CNS) structures.

For example, microparticles facilitating drug delivery to the central nervous system in the brain raises the question of fate of microparticles after their translocation to the specific cell types or to subcellular structures. This kind of questions includes whether mitochondrial localization induces oxidative stress and how persistent the coating or the core of nanoparticles is, which is essential in nanoparticle toxicology and safety evaluation⁴¹. The clearance of microparticles in the alveolar region is predominantly mediated by alveolar macrophages, through phagocytosis of deposited microparticles. After macrophages recognize the deposited microparticles and phagocytes them, macrophages with internalized microparticles gradually move toward the mucociliary escalator, and then the clearance process is started. The retention half-time of solid particles in the alveolar region based on this mechanism is very slow, up to 700 days in humans. Moreover, unlike larger particles, results from several studies show the apparent inefficiency of alveolar macrophage phagocytosis of micronized particles^{42, 43, 44}. The ultrafine microparticles are not easily phagocytized by macrophages and, consequently, are not readily cleared in the alveolar region⁴⁵. These porous microparticles are either in epithelium cells or are further translocated to the interstitium, which may cause a long-term accumulation in the lung and subsequent toxicity issues.

According to the FDA guidance for dry powder inhaler (DPI) drug products, alpha lactose monohydrate is the only approved sugar that can be used as a large carrier particle in dry powder inhalation aerosol products to fluidize and disperse the respiratory drug while it not being delivered to the lung. Other novel materials, including phospholipids, specifically lecithin and amino acids (lysine, polylysine) have also been developed for use in pulmonary formulations as excipients that are delivered to the lung. A thorough assessment of these alternatives associated with any inhalable substance is required, from a variety of sources human, animal, and/or in vitro test models⁴⁶.

CONCLUSION:

Inhalable macromolecule offers numerous advantages. The decrease in particle size leads to an increase in surface area leading to enhanced dissolution rate, as well as relatively uniform distribution of drug dose among the alveoli. In addition, by suspending the drugs in microparticles, one can achieve a dose that is higher than that offered by a pure aqueous solution, which is thermodynamically limited by the aqueous solubility of the drug. Macromolecular systems can provide the advantage of sustained-release in the lung tissue, resulting in reduced dosing frequency and improved patient compliance. Local delivery of inhalable macromolecule may be a promising alternative to oral or intravenous administration, thus decreasing the incidence of side effects associated with a high drug serum concentration. As with all formulations designed for pulmonary drug delivery of, potential long term risk of excipients toxicity and nanoscale carrier itself are issues that need to be considered in the successful product development of pulmonary drug delivery systems. Nevertheless, their inherently small size and surface modification properties enable further opportunities for innovative controlled drug release and pulmonary cell targeting therapeutic platforms. The integration of porous microparticle and pulmonary delivery has the potential to improve the targeting, release, and therapeutic effects of drugs.

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Received on 17.06.2010 Modified on 28.06.2010

Research J. Pharm. and Tech. 4(2): February 2011; Page 167-174

Sr no.	Polymer	Relative Mucoadhesive Force	Qualitative Bioadhesion property	Reference
1	Carbosymethyl cellulose	193	Excellent	32,48,49,50,51
2	Polycarbophil	-	Excellent	32,48,49,50,51
3	Carbopol	183	Excellent	32,48,49,50,51
4	Tragacanth	154	Excellent	32,48,49,50,51
5	Sodium alginate	126	Excellent	32,48,49,50,51
6	HPMC	125	Excellent	32,48,49,50,51
7	Gelatin	116	fair	32,48,49,50,51
8	Pectin	100	Poor	32,48,49,50,51
9	Acacia	98	Poor	32,48,49,50,51
10	Providone	98	poor	32,48,49,50,51