Pulmonary Drug Delivery Systems (PDDS)

Pulmonary Drug Delivery Systems

Session Outcomes

At the end of the session students will be to:

•       Explain significance of drug delivery to lungs

•       Describe anatomical and histological aspects of lungs

•       Enlist advantages and disadvantages of pulmonary route for drug delivery

•       Appraise challenges in pulmonary drug delivery

•       Discuss various pulmonary drug delivery systems

•       Recall latest develolpments in PDDS

Pulmonary Drug Delivery Systems

•       Pulmonary route used to treat different respiratory diseases from last decade.

•       The inhalation therapies involved the use of leaves from plants, vapours from aromatic plants, balsams, and myhrr.

•       Pulmonary drug delivery is primarily used to treat conditions of the airways, delivering locally acting drugs directly to their site of action.

•       Delivery of drugs directly to their site of action reduces the dose needed to produce a pharmacological effect.

•       The respiratory tract is one of the oldest routes used for the administration of drugs.Over the past decades inhalation therapy has established itself as a valuable tool in the local therapy of pulmonary diseases such as asthma or COPD (Chronic Obstructive Pulmonary Disease).

•       This type of drug application in the therapy of these diseases is a clear form of targeted drug delivery.

•       Currently, over 25 drug substances are marketed as inhalation aerosol products for local pulmonary effects and about the same number of drugs are in different stages of clinical development.

•       The drug used for asthma and COPD e.g..- β2-agonists such as  salbutamol (albuterol), Terbutalin formoterol, corticosteroids such as  budesonide, Flixotide or beclomethasone and mast-cell stabilizers such  as sodium cromoglycate or nedocromi,.

•       The latest and probably one of the most promising applications of pulmonary drug administration is

1)      Its use to achieve systemic absorption of the administered drug substances.

2)      Particularly for those drug substances that exhibit a poor bioavailability when administered by the oral route, as for example peptides or proteins, the respiratory tract might be a convenient port of entry.

Anatomy of Respiratory system

´  The human respiratory system is divided into upper and lower respiratory  tracts

´  The upper respiratory system consists of the external nose, nasal cavities,  nasopharynx and oropharynx mouth, trachea, nasal secretions

´  The lower respiratory tract consists of the larynx, bronchi, and alveoli,  which are composed of respiratory tissues

•       The human respiratory system is a complicated organ system of very close structure–function relationships.

The system consisted of two regions:

1.       The conducting airway 

2. The respiratory region.

·         The airway is further divided into many folds: nasal cavity and the associated sinuses, and the nasopharynx, oropharynx, larynx, trachea, bronchi, and bronchioles.

·         The respiratory region consists of respiratory bronchioles, alveolar ducts, and alveolar sacs

·         The human respiratory tract is a branching system of air channels with approximately 23 bifurcations from the mouth to the alveoli.The major task of the lungs is gas exchange, by adding oxygen to, and removing carbon dioxide from the blood passing the pulmonary capillary bed.

Lung region

1.       Nasopharynx region: (NP)

2.       Tracheobronchial region: (TB)

3.       Alveolar region: (AV)

Types of cells present in lungs

Bronchi

1)      Ciliated cells

2)      Goblet cells

3)      Serous cells

4)      Brush cells

5)      Clara cells

Bronchioles

1)      Ciliated cells

2)      Clara cells

Alveoli

1)      Type-1 pneumocytes

2)      Type-2 pneumocytes

Factors determining the deposition of inhaled particles

Advantages of Pulmonary Route Systemic acting drugs

ü  A large surface area for drug absorption

ü  Convenience and good patient compliance

ü  Rapid attainment of therapeutic drug levels in the blood

ü  High drug permeability, especially for lipophilic and low molecular weight drugs

ü  Avoidance of harsh environmental and gastrointestinal conditions

ü  Bypassing of hepatic first-pass metabolism

ü  Potential direct drug delivery to the brain along the olfactory nerves

ü  Direct contact site for vaccines with lymphatic tissues

Disadvantages

•       Complex delivery devices are required to target drugs to the airways and these devices may be inefficient.

•       Aerosol devices can be difficult to use

•       Various factors affect the reproducibility of drug delivery to the lungs, including physiological (respiratory maneuver) and pharmaceutical (device, formulation) variables.

•       Drug absorption may be limited by the physical barrier of the mucus layer and the interactions of drugs with mucus.

•       Mucociliary clearance reduces the retention time of drugs within the lungs. Efficient drug delivery of slowly absorbed drugs must  overcome the ability of the lung to remove drug particles by mucociliary transport

Advantages of Pulmonary Route Locally acting drugs

Targeted Delivery

•          Drug is deposited its site of action

•          Systemic absorption and distribution throughout the  body not required

•          Effectiveness not limited by poor absorption or hepatic first-pass metabolism

Clinical advantages

•          Low dose compared to oral therapy

•          Low incidence of systemic side-effects

•          Rapid onset of drug action

CHALLENGES IN PULMONARY DRUG DELIVERY

q  Low Efficiency of inhalation system

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 effects on the oropharynx and larynx. (0.5-1mm)

q  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.

q  Poor formulation stability for drug

Most traditional drugs are crystalline, in the case of corticosteroids, and highly moisture sensitive drugs are unstable.

q  Improper dosing reproducibility

Reason for Poor dosing reproducibility like worsening of diseases’, problem in device, unstabality of formulation.

Nasal Preparations for systemic effect

Ø  Butorphanol

Ø  Sumatriptan

Ø  Desmopressin

Ø  Insulin

Butorphanol

It is a potent synthetic mixed agonist-antagonist opioid analgesic

Butorphanol for nasal administration is marketed as Stadol NS Nasal spray

It is a metered spray having an aqueous solution of butorphanol tartrate with sodium chloride, citric acid and benzelthonium chloride

Sumatriptan

Ø  It is a serotonin receptor agonist,

Ø  used in the treatment of migraine  and cluster headache

Ø  It offers several advantages:

Ø  Ease of self- administration  unlike injections

Ø  Better bioavailability in comparison to oral (only 14%)

Ø  Convenient in cases of nausea and vomiting unlike oral tablets

Ø  A marketed nasal formulation of sumatriptan is Imigran (Glaxo  Wellcome)

Desmopressin

´  It is the synthetic analogue of the naturally occurring antidiuretic hormone,  vasopressin

´  It is one of the First example of peptide drugs that were administered nasally for  systemic effects

´  Traditionally, it was administered using the rhinyl catheter method as drops or by  metered –dose pump as spray

´  DDAVP^® Nasal spray (desmopressin acetate) or DDAVP^® Rhinal Tube are available  as aqueous solutions containing desmopressin acetate

Insulin

It is used in the therapy of diabetes mellitus

Till date, several trials have been carried out with intranasal formulations but only with low and variable bioavailability and uncertainty about long- term safety

Challenges in Pulmonary Drug Delivery

Assessment of Pulmonary Drug Delivery

Lung Deposition (radionuclide imaging)

Pulmonary bioavailability (pharmacokinetic)

Inhaler Devices

Correct inhaler technique

Non suitable devices for >1 mg drug dose

Lung defense mechanisms

Evolved to prevent entry of inhaled materials

To remove them once deposited

·         Controlled pulmonary drug delivery is a big challenge because different parts of the respiratory tract are cleared by different mechanisms

·         PLGA nanoparticles have been investigated for pulmonary delivery of anti-TB drugs

Dosage forms for pulmonary drug delivery

Aerosol

•       Aerosol is a pressurized dosage forms containing one or more  therapeutic active ingredients which upon actuation emit a fine  dispersion of liquid or solid materials in a gaseous form

•       The particle size of aerosols  important in determining the disposition site

Aerosol particle size on the dispersion pattern

Particle diameter  (μm)	Deposition site	Deposition per cent
≥10	Oropharynx	100%
>5	Central airways  (tracheobronchial)	20%
<3	Peripheral airways  (alveoli)	60%
	Extrathoracic	~10%

Determination of Particle Size

a)      Cascade Impactor

Principle- Stream of particles projected through a series of nozzles and glass slides at high velocity larger particles are impacted first on lower velocity stage and smaller particles are collected at higher velocity stage

b)      Light Scattering Decay

Principle- As aerosol settles under turbulent conditions the change in the light intensity of a Tyndall beam is measured

Advantages

•          A dose can be removed without  contamination of materials

•          Ease and convenience of  application

•          Rapid response to the medicament

•          Irritation produced by mechanical  application is eliminated or reduced

Disadvantages

•          Expensive

•          Inflammability

•          Toxicity

•          Explositivity

•          Bronchoconstriction

Inhalation Drug Delivery System

The respiratory tract has been largely used for treatment of obstructive airway diseases (e.g. Asthma)

It can be classified into:

1. Nebulisers

2. Metered dose inhalers

3. Dry powder inhalers

Nebulizers

•       ´Nebulizers have been successfully employed for drug delivery to  lungs

•       ´It has also been examined for local drug delivery to the trachea as  for local anaesthesia for bronchoscopy

Metered Dose Inhalers

´The development of first pressurised MDI in the mid- 1950s has been major advance in the administration of drugs locally to the lungs especially for the treatment of asthmatics

•       MDI composed of four components viz

Ø  Base formulations (drug, propellant, excipients)

Ø  The container

Ø  The metering valve

Ø  The actuator (mouthpiece)

Metered Dose Inhalers Merits

Ø  Multi-dose capabilities

Ø  Quick delivery

Ø  Pressurised inhaler protects from  ingress of both moisture and  pathogens

Metered Dose Inhalers Demerits

Ø  Difficult for people with  osteoarthritis affecting hands

Ø  May be unsuitable for patients  with severe COPD with poor  inspiratory flow rate

Ø  pMDIs require coordinating your  breath with medication release  (inhaling technique)

Ø  Much of the dose is deposited in  the oropharynx

Ø  An inspiration flow rate of  25L/min is required

Dry powder Inhalers

´  DPIs are an alternative to the aerosol based inhalers commonly MDIs, that  deliver a powder dosage form to the lungs

´  These devices are environmental friendly since they do not require CFC  propellants for drug dispersion

´  DPIs are also versatile devices

´  They are commercially available in two types

ü  Unit dose devices

ü  Multidose devices

Inhalation Drug Delivery System Applications

1. Targeted treatment of lung disorders
2. Non-invasive alternative to injection for macromolecule drugs (biologicals)  such as insulin
3. Efficacious and patient-friendly vaccines (pain free)

Novel Approaches for Pulmonary Delivery

·         ´Polymeric nanoparticles

·         ´Liposome

·         ´Solid lipid nanoparticles

·         ´Submicron emulsion

·         ´Dendrimer-based nanoparticle

Polymeric Nanoparticles

´  Carriers for drug molecule

´  Prevent drug from degradation

´  Control of drug release

´  Due to their biocompatibility, surface modification capability, and sustained-  release properties, polymeric nanoparticles are intensively studied using  various important pulmonary drugs

´  Additionally, In-vitro lung surfactant models and In-vivo studies are required  to establish the pulmonary acceptability of polymeric nanocarrier systems

Liposomes

·         ´Most extensively investigated systems for controlled delivery of drug to the lung

·         ´Appropriate for therapeutic agent delivery to lung, since these vesicles can be prepared from compounds endogenous to the lungs, such as the components of lung surfactant, and these properties make liposome attractive candidate as drug delivery vehicles

·         ´Synthetic lung surfactant Alveofact^® for pulmonary instillation for the treatment of respiratory distress syndrome

·         ´Typically, liposomal formulations have been delivered to the lung in the liquid state, and nebulizers have been used extensively for the aerosol delivery of liposomes in the liquid state

·         ´Liposomal dry powder formulations have been intensively examined in order to successfully circumvent these issues and some of them are in clinical trials

·         ´Liposomes conjugated with cell-penetrating peptides are recognized as potential nanocarrier systems for intracellular delivery of macromolecules to the lung

Solid Lipid Nanoparticles

·         ´The advantages of drug release from SLNs in the lung are control of the release profile, achievement of a prolonged release and having a faster In-vivo degradation compared to particles made from PLA or PLGA

·         ´Pulmonary applications of SLNs as local delivery carriers for small molecules or as systemic delivery carriers for macromolecules have been reported

·         ´SLNs incorporating rifampicin, isoniazid and pyrazinamide are evaluated against experimental tuberculosis, and observed the slow and sustained-release of drugs from the SLNs both In-vitro and In-vivo

• Deposition and clearance of SLNs were assessed after inhalation of aerosolized  insoluble particles using gamma-scintigraphy imaging analysis
• Inhaled material began to translocate to regional lymph nodes indicating that  inhalation can be an effective route to deliver drug-containing lipid particles to  the lymphatic systems and lipid particles can be used as potential drug carriers for  lung cancer therapy, as well as for vaccine delivery

Submicron emulsions

´  Submicron emulsions are promising carriers for DNA vaccines to the lung  since they are able to transfect pulmonary epithelial cells, which possibly  induce cross priming of antigen-presenting cells and directly activate  dendritic cells, resulting in stimulation of antigen-specific T-cells

´  Submicron emulsion loaded with Mycobacterium tuberculosis Ag85B DNA  vaccine was explored for the purpose of pulmonary mucosal vaccination

 

Dendrimer-based nanoparticles

•       Cationic dendrimers can be used as pulmonary delivery carriers for a relatively  large molecular weight anionic drug

•       Binds anionic drug molecules most likely via electrostatic interactions and increase  drug absorption through charge neutralization

•       Half-life and absorption of LMWH administered via the pulmonary route can be  increased by encapsulating the drug in dendrimeric micelles

•       LMWH loaded in the mPEG–dendrimer could potentially be used as noninvasive delivery system for the treatment of thromboembolic disorder

Emerging Delivery Techniques

The AERx^® System (Aradigm Corporation)

“Intelligent” inhaler

•          Records inhaled flow rate

•          Breath-actuated at pre-  determined volume / flow

•          Dose titration

•          Dose-recording history  Aerosol formation

•          Heater helps control aerosol  size

•          Nozzle hole diameter 1.2 μm  Drug doses > 20 mg in 45 μL  possible

•          Nano-suspensions also  possible

Respimat^® Soft Mist^TM Inhaler (Boehringer Ingelheim)

•       Respimat SMI is a “press and breathe” device

•       Low spray velocity and long  duration aerosol cloud assumed to  make coordination easier

•       Clinical trials demonstrate clinical  efficacy with ¼ to ½ of the pMDI or  Handihaler^® DPI dose

•       Corresponds to improved lung  deposition

•       Being developed primarily for

•       drugs to treat COPD

•       Launched 2004: fenoterol /  ipratropium bromide (Berodual^®)

Advantages of AERx^® System

Ø  Lighter and smaller than electronic device

Ø  Similar efficiency and reproducibility

Ø  No heater, dose titration, dosing  history recording

Ø  600 nm diameter nozzle

Ø  holes by laser photoablation

Future Prospects

Lung Model

•          Weibel Model of  Lung

Simulation studies

•          Device Characteristics

•          Deposition Behavior

Conclusion

´Drug delivery through the respiratory tract has been used for local and systemic effects, it offers considerable advantages over alternative routes of administration for delivering drugs to systemic circulation

´The success of various novel drug delivery carries nasopulmonary delivery ultimately depends on the ability to produce sufficiently stable formulation that can be practically administered through available devices

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