Transcript Pulmonary drug delivery system

Pulmonary drug delivery system

Currently, over 20 drug substances are marketed as inhalation aerosol product for local
pulmonary effect and about the same number of drugs are in different stage of clinical
development

pulmonary drug delivery systems:
1: Disease of respiratory tract for asthma,
2: For systemic delivery via the drug
Unique advantages of pulmonary rout

high permeability

large absorptive surface area of lungs(approximately 70-140 m2 in
adult humans having extremely thin absorptive mucosal membrane)

good blood supply

low enzymatic activity

rapid absorption of drug

capacity for overcoming first-pass metabolism
Advantages of pulmonary delivery
Advantages of pulmonary rout for systemic
delivery

Improved efficiency

Reduced unwanted systemic side effect

Large surface area for absorption

Tine alveolar epithelium permitting rapid absorption

Absence of first pass metabolism

Rapid onset of action
Human airways
1: conduction region:


The drug transport is limited due to smaller surface area
and lower regional blood flow.
this region removes up to 90% of delivered drug particles
2: respiratory region

for more than 95% of the lung’s surface area

directly connected to the systemic circulation via the
pulmonary circulation
Bronchial circulation

Only alveolar region and
respiratory bronchioles are
supplied by the pulmonary
circulation

Blood flow to the larger
airways is via the systemic
circulation (0.1 % cardiac
output)(bronchial circulation)
limitations of pulmonary rout for systemic
delivery
1: oropharyngeal deposition gives local side effect
2: Patients may have difficulty using pulmonary drug delivery device
correctly
3: Inefficiencies of available inhalation devices that deposit only 1015% of the emitted dose in the lung
4: Drug absorption may be limited by the physical barrier of the
mucus layer
5: Various factors affect the reproducibility on drug delivery on the
lung, including physiological and pharmaceutical barrier
Lung deposition of particles

Deposition of drug/aerosol in the airways depends on four
factors:
1: The physic-chemical properties of drug
2: The formulation
3:The delivery device
4: Physiological factor(breathing pattern and clinical status)
Definition of aerodynamic diameter and fine particle fraction

The particle size of aerosol is usually standardized by calculation of its
“aerodynamic diameter” to deliver particle to different are of lung

it depends on size, shape, and density of the particulate system

Da= Dp √ρ

Fine particle fraction (FPF)

The fraction of particles of particles that can achieve deposition in the lower
respiratory tract
Particles between 0.1-1 µm
remain suspended, these particles
tend to be exhaled rather than
deposited
maximum deposition is obtained
in the pulmonary region for
particles approximately 3µm in
size
Lung deposition occurs mainly by 3 mechanisms
1
1: Inertial impaction
Particles >5µm and particularly > 10 µm are deposited by this mechanism
2: Gravitational sedimentation
2
Particles 1-5 µm are deposited by this mechanism
U= ρgd2/18ŋ
3
3: Brownian motion
Smaller than 0.5 µm
Dp=CKT/3πdŋ
>5 µ
1-5 µ
≤1 µ

Alton pharmaceutics Pulmonary drug delivery

Pulmonary drug delivery. Part I: Physiological factors affecting
therapeutic effectiveness of aerosolized medications 2003
Blackwell Publishing Ltd Br J Clin Pharmacol, 56 588–599

Pulmonary drug delivery. Part II: The role of inhalant delivery devices and drug
formulations in therapeutic effectiveness of aerosolized medications Br J Clin
Pharmacol 56 600–612
Physiological factors affect deposition in the air way
1: Respiratory flow rate (RFR)
Low flow rate reduce impaction in larger airways
2: Tidal volume
Volume of air inhaled in one breath
3: Breath holding
Prolonged breath hold allow greater time for sedimentation and diffusion to occur in the
peripheral airway
Increasing the time between the end of inspiration and the start of exhalation increases the
time for sedimentation to occur
4: Disease statute
Bronchial obstruction result in localized deposition in larger airway
Health care providers should ensure that their patients can and will use these device
correctly
Lung clearance mechanism
 Once
deposited in the lung, inhaled drugs are either:
1: cleared from the lungs,
2: absorbed into systemic circulation
3: degraded via drug metabolism
Lung clearance mechanism
mucociliary clearance
Drugs deposited in the conducting airways

Drugs deposited in the alveolar region
absorption into the bronchial
circulation
absorbed into the pulmonary
circulation
phagocytosed by alveolar
macrophages
All metabolizing enzymes found in the liver are found to a lesser extent in the
lung
Lung clearance mechanism
Challenges in pulmonary drug delivery

Low efficiency of inhalation system

Less drug mass per puff

Poor formulation stability for drug

Improper dosing reproducibility

Lung clearance
Formulating and delivering therapeutic
inhalation aerosols
It is the optimization of the whole system
including drug formulation, and device for
successful development of inhalation
therapies

There are currently four main types of aerosol
generating
1: conventional pressurized aerosols
2: pressurized metered-dose inhalers (MDI)
3: dry powder inhalers (DPI)
4: nebulizers.
conventional pressurized aerosols

Space sprays

Surface spray

Aerated spray

Inhalation aerosols
drug is either dissolved or suspended in liquid propellant(s) together with other
excipients, including surfactants, and presented in a pressurized container
‫محاسن آیروسل ها‬
‫مقدار مورد نیاز دارو برای هربار مصرف به راحتی می‬
‫تواند از ظروف برداشته شود بدون اینکه باقیمانده‬
‫آلوده شود‬
‫فراورده از اکسیژن هواونور محفوظ بوده وهمین طور‬
‫استریل بودن فراورده باقی نگه داشته می شود‬
‫استعمال یکنواخت دارو روی موضع بدون تماس با سطح‬
‫پوست هیچ گونه تحریک زایی مکانیکی وجود نخواهد‬
‫داشت‬
‫تبخیر سریع پروپالنت یک احساس مطلوب خنک وتازه ای‬
‫پروپالنت‬
‫عبارت است از یک یا مخلوط چند گاز مایع شدنی یا مایع‬
‫نشدنی کمپرس پذیر‬
‫پروپالنت دونقش دارد‪:‬‬
‫منبع ایجاد فشار درسیستم‬
‫نقش حالل‬
‫انواع پروپالنت ها‪:‬‬
‫گازهای مایع شدنی‬
‫کلرو فلوروکربن ها‬
‫گازهای کمپرس شده ای که به حالت مایع درنمی اید‬
‫کربن دی اکساید نیتروژن ونیتروس اکساید‬
chlorofluorocarbons
HFA-134 and HFA-227 are nonozone depleting, non-Flammable HFAs, which are now
used as alternatives to CFC-12
‫انواع سیستم های آیروسل ها‬
‫سیستم ها ی‬
‫دوفازی‬
‫سیستم های سه فازی‬
‫درتهیه آیروسل ها ممکن است مخلوطی‬
‫ازگازهای مایع شدنی استفاده گردد‪:‬‬
‫رسیدن به یک فشاربخار مطلوب‬
‫تهیه یک حالل مناسب برای انحالل دارو‬
‫فشارنسبی درفرموالسیون آیروسل ها‬
‫فشار را می توان با نوع ومقدار پروپالنت تنظیم نمود‬
‫فشاربخار مخلوطی از پروپالنت ها توسط قانون رایولت بیان می‬
‫شود‬
‫‪P = p a + pb‬‬
‫‪Pa= Xa P○a‬‬
‫فشار بخار مخلوط ‪ 60‬به ‪ 40‬پروپان وایزوبوتان چقدر است‬
‫‪10.23‬‬
‫‪0.69+0.69/1.36‬‬
‫‪)0.69+1.36(/1.36‬‬
‫‪1/36=60/44.1‬‬
‫=‬
‫*‪72.98=110‬‬
‫‪0.69=40/58‬‬
‫*‪30.40‬‬
‫‪Metered dose inhalers‬‬
‫این سیستم ها دوز مورد نظر را اندازه گیری و‬
‫تنظیم می نماید‬
‫مقداری از فراورده که الزم است به بیرون رانده شود‬
‫به وسیله یک محفظه که حجم آن مشخص است تنظیم می‬
‫شود‬
‫حجم این محفظه می تواند بین ‪ 25‬تا ‪150‬‬
‫میکرولیترباشد‬
‫این نوع سیستم ها به دودسته تقسیم می شوند‬
‫نوع ایستاده‬
‫نوع معکوس‬
Advantages of MDI

Low cost

Many doses (up to 200) are stored in small canister

Dose delivery is reproducible

Protect drugs from oxidative degradation and
microbiological contamination
disadvantages of MDI
high velocity (30 m/s)

They are inefficient at drug delivery
Propellants may not
evaporate sufficiently
(5 s after actuation)

Cold-freon effect
disadvantages of MDI






failure to remove the protective cap covering the mouthpiece
failure to inhale slowly and deeply
inadequate breath-holding following inhalation
poor inhalation/actuation synchronization
Correct use by patients is vital for effective drug deposition and therapeutic
action.
pMDI should be actuated during the course of a slow, deep inhalation, followed
by a period of breath-holding.
Advantages of spacer
 no
co-ordination requirement
 No
cold-Freon effect
 Reduced
oropharyngeal deposition
 Increased
lung
drug deposition in the
Novel technology in MDI

Breath-actuated MDI

increase lung drug deposition from 7.2% to 20.8%

Do not help stop inhaling at the moment of actuation (cold-freon)

The oropharyngeal dose remains the same as for the MDI device
Autohaler
AUTOHALER
syncroner
‫عملیات پرکردن آیروسل ها‬
‫‪ :1‬پرکردن تحت سرما‬
‫سیستم های آبی را به این روش نمی‬
‫توان به ظرف آیروسل منتقل کرد‬
‫‪ :‬پرکردن تحت فشار‬
‫پروپالنت کمتری درپروسه پرکردن به هدر‬
‫می رود‬
‫خطر آلودگی بارطوبت وجود ندارد‬
Dry powder inhalers (DPI)

ADVANTAGES:

Elimination the co-ordination difficulties associated with MDI

Elimination CFC-containing MDIs

DPI can also deliver larger drug doses than MDIs

DPI are very portable

Patient friendly

Easy to use and do not require spacers
Dry powder inhalers

DISADVANTAGES

Deagregation of particles and aerolization depend on the patient
ability to inhale

Increase inhaled air velocity increases the deagregation of particle,
but increase inertial impaction

DPI are less efficient at drug delivery than MDI

the effectiveness of DPI depends on :
1: The properties of the powder formulation

Reducing Da
agglomeration

Reduce particle density

Increasing particle shape factor
reduce Dg
increase particle cohesive force
reduce aerolization
greater
introduce porosity
using needle shape particle
2: The design of device
3: patient respiratory air flow

Increasing the IFR from 35 l/min to 60 l/min thrugh Turbuhaler increased the total
lung dose of terbutaline from 14.8 to 27.7
DPI formulations

For topical respiratory drug

For systemic delivery PZ: less than 3 micron
that adhere to larger carrier particles such as
lactose or as drug only agglomerate

The purpose of adding carriers:
PZ:2-5 micron
1: To reduce strongly cohesive agglomerate
2: Increase the flow ability of powder prior to
aerolisation
Performance of existing DPI

There are three main types of DPI
systems:
1; The single unite dose inhaler
2: Multi unite device deliver individual
doses from pre-metered replaceable
blisters
3: Multiple dose reservoir inhaler
The single unite dose inhaler

Spinhaler

Rotaheler

Handihaler

Rotacap

Revolizer

Needs a sequence steps that may not be easy for children
and elderly people

The capsule may not always protect the formulation against
atmosphere humidity

Spinhaler and rotahaler very low resistance while rotacape
needs high flow rate
Multi unite device deliver individual doses
from pre-metered blisters

Diskus inhaler containing 60
doses

It is not refillable and the
mouthpiece is not userfriendly

The production cost is high

Diskus (accuhaler) low to
moderate resistance multi unite
dose device
Multiple dose reservoir inhaler

Turbuhaler is the highest resistance device (60 l/min)

Easyhaler

Clickhaler

Less independent of flow rate compared to
that of turbuhaler
active device

Active device with an inspiration actuated integrated energy source
such as compressed gas motor driven impeller or electronic
vibration are under investigation

Respiratory force independent useful for aged people

Exubera insulin delivery used compressed air

Aspirair (not yet approved) employs an air flow sensor triggered
compressed air energy and a vortex chamber
Recent innovation in DPIs

There are two generation approaches to improve the effectiveness
of DPI

1: develop better device

Better powder

NEXT a multi unit device accurate dose metering and protection
the drug from environment easy to use and cost effective

Twincer moisture sensitive high powder dose

Microdse a breath actuated and piezo-electronic device
Characteristics of an ideal DPI device

Simple to use, convenient to carry, contains multiple dose, protect the drug from
moisture and has indicator of doses remaining

Dose delivery which is accurate and uniform over a wide range of IFR

Optimal particle size of drug for deep lung delivery

Minimum adhesion between drug formulation and device

Product stability

Cost-effectiveness

Presently, over 20 DPI devices are available in market and more than 25 are in
development
nebulizers

There are two basic types of nebulizers:

Jet nebulizerss

Compressed gas (air or oxygen) passed through a narrow
orifice creating an area of low pressure

Ultrasonic nebulizers

Uses piezoelecteric crystal vibrating at high frequency (13 MHz)

Provide large dose with very little patient co-ordination

Time consuming and inefficient with large amount of drug
wastage(50% loss with continuously operated nebulizer)

Only 10% of the dose actually deposited in the lung

Viscosity, ionic strength, osmolarity, ph, and surface tension may
prevent the nebulization
Inhaled drug formulation
Drug formulation plays an important rule for efficient inhalation
medication
1: to have a drug that is pharmacologically active
2: efficiently deliver to the lung
3: remain in the lung until the desired pharmacological effect
occurs
Principle of dry powder inhaler design
Dry powder inhaler formulations
The effective dispersion of drug particles depends on:
1: Cystalinity and polymorphism
2: Morphology
3: Surface area
4: Moisture content and hygroscopicity
5: Particle size and size distribution
6: Density
7: Adhesion/cohesion force
Crystalinity and polymorphism

Most drugs are crystalline

On third of all drugs are known to display polymorphism

With different properties such as stability, solubility

It is possible to generate noncrystaline solid

Amorphous materials have higher Gibbs free energy

Crystaline particles are typically nonsphercal, low energy surface,
and stable, but they have high particle density and tend to pack
more tightly
Moisture content and hygroscopicity
Hygroscopic drugs present a greater risk of physical and chemical
instability
Hygroscopic growth can be prevented by coating the drug particles with
hydrophobic film
However, no such approach has been successfully implanted in market
Aerodynamic diameterand dynamic
shap factor
X: the ratio of the
actual resistance
force experinced
by the non
spherical falling
particle to the
resistance force
experience by a
shere having the
same volume
Fine particle
fraction:
percantage of
An ideal respiratory dry powder formulation
should:

An ideal respiratory dry powder formulation should have:
1: Narrow aerodynamic particle size range
2: Low surface energy
3: Non-spherical morphology
4: Low density or high porosity
5: High physical and chemical stability
Carrier particles

Lactose is commonly used

The crystallinity of lactose carrier plays an important role in the aerosol
performance of DPI formulation

Amorphous lactose carrier exhibit strong adhesive interaction with drug molecules
low inhalation efficiency

Conventional α-lactose monohydrate ≥ spray-dried amorphous lactose

Another problem of amorphous carrier
humidity

Reduce the amorphous content or increasing the crystalinity of the lactose
recrystalization and higher relative
Carrier particles

Surface roughness of lactose is also important

Various techniques have been applied to smooth carrier particle surface
1: Dry coating with hydrophobic lubricant
magnesium stearate
2: Wet coating with hydrophilic polymers
sucrose tristearate,
HPMC
3: Surface dissolution with organic solvent 70% ethanol

Safety issue?
Carrier particles

The presence of a small amount of adhered fines (5 µm) on coarse lactose is
critical for facilating particle deagregation in air turbulence generated by inhalation

This can be accomplished by fluidized bed coating of micronized lactose particles
with dissolved lactose in spray solution

One drawback: lactos is reducing suger which make it incompatible with drugs that
have primary amine group formetrol, peptids, proteins

Manitol has emerged as a promising carrier

Higher respirable fraction with budesonide compared with lactose
Carrier particles

One drawback: lactose is reducing sugar which make it incompatible
with drugs that have primary amine group
formetrol, peptides,
proteins

Manitol has emerged as a promising carrier

Higher respirable fraction with budesonide compared with lactose
Different techniques to produce inhalable particles
1: milling techniques
2: Spray drying technique
3: Spray freeze drying method
4: Supercritical fluid technology
5: Solvent precipitation method
Milling techniques

Fluid-energy mill

The most useful milling technique

High velocity particle-particle
collisions

Depends on the nitrogen pressure and
powder feed rate
particle
down to 1µm
jet mill
Pin mill
High peripheral speed mill
pin mill
A pin mill uses mechanical impact to grind
material both by particle-particle and particlesolid collisions
The pin mill can produce 1 micron particle but
not as small as jet mill
The energy consumption is lower than jet mill

Ball mill

Particle shap is near spherical
Milling can induce electrostatic
charges and generating
amorphous domains on
particle surface
Inceasing cohesive and adhesive
force
The materials are also prone to
chemical decomposition and
water sorption

In summary, although micronization is well developed for size reduction

It is not sutable for fragil molecules and more complex structure such as
hallow particle, nonspherical particle, composite, surface modified
particles, coated and encapsulated particles
Milling techniques
reference

Formulation strategy and use of excipients in pulmonary
drug delivery, Int J pharmaceutics 2010 392 1-19
Spray drying

Is a one step process that converts a liquid feed to a dry particulate

Three operations of the spray drying include: atomization, drying and
separation

The feed can be: solution, a coarse fine suspension or a colloidal
dispersion( emulsion, liposome, and nanoparticle)

Open cycle: the drying gas (compressed air) is not recirculated and, is
vented to the atmosphere

Close cycle: the heated gas (nitrogen with less than 5% oxygen) is
recirculated
Spray drying

Advantages

This method is suitable for heat labile materials used for peptides
and proteins

Produced more spherical particle compared to milling with more
homogeneous particle size distribution

Particles from spray drying process are not always spherical and
may have convoluted surface, asperities, hole, and voids.
Advantages
Ability to manipulate and control a variety of parameters:

solvent composition,

solute concentration,

solution and gas feed rate,

temperature and

relative humidity

droplet size
Spray drying disadvantages

Thermal stress, higher shear stress in nozzle, and peptide protein
adsorption
 Polysorbate 20 has been used to reduce spray drying induced
denaturation for human growth hormone

Low yield value esp for particle below 2 micron (yeild 20-50%)
 Spray-dried particles from solutions are mostly amorphous, but to
maintain the crystalline state suspension can be processed
Large porous particles
 Pulmospheres®

They have low particle densities, excellent dispensability

Mass density 0.4 g/cm3 and geometric diameter > 20 µm

They were prepared by solvent evaporation and spray drying techniques

In two step process: 1: an oil in water emulsion by high-pressure homogenization using
phosphatidylcoline as the surfactant and fluorocarbons serve as a blowing agent

2: spray drying of the emulsion
Large porous particles
Cromolyne pulmosphere have 68% compared with 24%
Increase systemic bioavailability of Insulin and testosterone
using this technology
Large porous particles

Advantages

Large porous particles allow for escape from natural phagocyte clearance

Reduces their tendency to aggregate and makes them more responsive to shear
in an airflow path

For potent, low-dose drugs these particles can be excellent delivery system

Particle size, morphology and density can be controlled through the selection of
the blowing agent type, and its concentration
Spray-freeze drying (SFD)

Spraying a solution containing the drug into vessel containing
liquid nitrogen, oxygen, or argon

Conducted at subambient temperature

Has been used to formulate a significant number of thermolabile
and highly potent proteins and peptides

It is faced with the limitations of stresses associated with freezing
and drying
irreversible damage to the proteins

This technique is time consuming (3 days), and safety issue and it is
expensive
Spray-freeze drying (SFD)

SFD produced very fragile particle, which can not withstand
production process of an adhesive mixture

Adsorption of proteins at air-liquid interface during atomization is
mainly responsible for loss of activity during spray drying and
SFD

1: spray freezing into liquid

2: spray freezing with compressed co2
Supercritical fluids

The particles produced via SCF are less charged compared with
mechanical means

They are more uniform in terms of crystalline, morphology and
particle size

Denaturating effects of the solvents/antisolvents used in this
process is a drawback
As conclusion

Spray drying and supercritical fluid methods offer more flexibility
and the possibility of control over morphology and size

But produce amorphous materials and undesired polymorphism

Milling remain the process of choice for micronizing because it is
simple, more predictable, easier to scale up and less expensive
List of accepted additives for DPI formulation
lipids

The surfactant present in the lung is composed of
90 % lipids and 10% proteins

Saturated fatty acid
dipalmitoylphosphatidylcholine (DPPC) 40%

Unsaturated phosphatidyllcholines 35%

Liposomes are the most extensively investigated
systems for pulmonary delivery
liposomes

Cytotoxic agents, anti-asthma drugs, antimicrobial and antiviral agents

Drugs for systemic action such as insulin and proteins

Liposome are known to promote an increase in drug retention time and
reduce cytotoxicity

For amikacin

The overall mean retention at 24h and 48h was 60% and 38%,
respectively

They are commonly delivered either in aqueous form via nebulization or
in dry powder form
total lung deposition 32%
liposomes

Liposome in the rang of 50-200 nm would avoid phagocytosis

In future liposome playing a prominent role in pulmonary delivery for gen therapy,
sustained release preparations and for targeting specific cell to treat intracellular
infection and local tumor cells

Francisella tularents reside and multiple in macrophages

Liposome encapsulated ciprofloxacin survived 15 days post infection compared
with100 mortality during 9 days

Pulmonary delivery of liposomal formulation of antibiotic
lipids

Lipids coat the drug particles with hydrophobic film that protect the
hygroscopic drug like tubramycine from humidity

Only 5% lipid is sufficient to improve particle dispersion properties

FPF 36% to 68% of effective lipid-coated formulation

Lipids in general are the excipient of choice because they are
mostly endogenous to the lung and can be easily methabolized or
cleared
List of accepted additives for DPI formulation
Amino acids

Recently amino acids have been shown to decrease hygroscopisity and improve
surface activity and charge density of particles

Glycine, alanine, leucine, isoleucine

Addition of amino acids to inhalation formulation using spray drying
improve in-vitro deposition profiles

Amino acids can also protect proteins against thermal stress and denaturation

Have been used as cryoprotectant
Amino acids

Addition of Leucin yeild the best results in term of aerolization

10-20 %w/w of leucin in spray-dried solutions gave optimal aerolization
of powder containing peptidies

Addition of leucine results in less cohesive particle due to the surfactant
behavior of leucine , decrease particle size

Little is known about the local toxicity and systemic absorption
List of accepted additives for DPI formulation
surfactants

Sorbitan, polysorbate, sorbitan esters have been widely used in
formulation of nebulization and MDI

Their use in DPI is not widespread due to their low melting
point and their semisolid or liquid state

Poloxamer or phosphatidylcholine to prepare hallow particle

2% poloxamers significantly improved powder flowability
Absorption enhancer

Cyclodexterins (CDs) improvement in aqueous solubility, systemic
absorbtion and bioavailability in vitro study safe at 1 m M
 Hydroxypropylated B-CD and natrul ƔCD


Protease inhibitors: nafamostate mesilate, bacitracin
Bail salt increase transcellular transport
 Administration of sodium taurocholate with insulin increase
bioavailability from 2.6 to 23
Absorption enhancer

More than 10 mm sodium glycocholate is harmful

Bile salt may be useful in small amount

Citric acid has been increased insulin absorption

Citric acid is considered a safe and effective absorption enhancer
for pulmonary delivery

Chitosan and trimethylchitosan absorption enhancers for proteins
and peptides significant pulmonary inflammation
Biodegradable polymers